J. Pineal Res.

2012; 52:167202

 2011 John Wiley & Sons A/S

Journal of Pineal Research

Doi:10.1111/j.1600-079X.2011.00937.x

Molecular, Biological, Physiological and Clinical Aspects of Melatonin

REVIEW ARTICLE

Alzheimers disease: pathological mechanisms and the beneficial

role of melatonin
Abstract: Alzheimers disease (AD) is a highly complex neurodegenerative
disorder of the aged that has multiple factors which contribute to its etiology
in terms of initiation and progression. This review summarizes these diverse
aspects of this form of dementia. Several hypotheses, often with overlapping
features, have been formulated to explain this debilitating condition. Perhaps
the best-known hypothesis to explain AD is that which involves the role of
the accumulation of amyloid-b peptide in the brain. Other theories that have
been invoked to explain AD and summarized in this review include the
cholinergic hypothesis, the role of neuroinammation, the calcium
hypothesis, the insulin resistance hypothesis, and the association of AD with
peroxidation of brain lipids. In addition to summarizing each of the theories
that have been used to explain the structural neural changes and the
pathophysiology of AD, the potential role of melatonin in inuencing each
of the theoretical processes involved is discussed. Melatonin is an
endogenously produced and multifunctioning molecule that could
theoretically intervene at any of a number of sites to abate the changes
associated with the development of AD. Production of this indoleamine
diminishes with increasing age, coincident with the onset of AD. In addition
to its potent antioxidant and anti-inammatory activities, melatonin has a
multitude of other functions that could assist in explaining each of the
hypotheses summarized above. The intent of this review is to stimulate
interest in melatonin as a potentially useful agent in attenuating and/or
delaying AD.

Sergio A. Rosales-Corral1,2, Dario

Acuna-Castroviejo3, Ana CotoMontes2, Jose A. Boga2, Lucien
C. Manchester2, Lorena FuentesBroto2, Ahmet Korkmaz2, Shuran
Ma2, Dun- Xian Tan2 and Russel
J. Reiter2
1

Centro de Investigacion Biomedica de

Occidente del Instituto Mexicano del Seguro
Social, Guadalajara, Jalisco, Mexico;
2
Department of Cellular and Structural Biology,
University of Texas Health Science Center at
San Antonio, San Antonio, TX, USA;
3
Departamento de Fisiologa, Instituto de
Biotecnologa, Universidad de Granada,
Granada, Spain

Key words: Alzheimers disease, amyloid-b

peptide, calcium, cholinergic
neurotransmission, free radicals,
inflammation, insulin resistance, melatonin,
oxidative stress

Address reprint requests to Sergio A. RosalesCorral, Centro de Investigacion Biomedica de

Occidente del Instituto Mexicano del Seguro
Social, Sierra Mojada 800 colonia Independencia, Guadalajara, Jalisco, CP 45150,
Mexico.
E-mail: espiral17@gmail.com
Received September 30, 2011;
Accepted October 4, 2011.

Introduction
Alzheimers disease (AD) is a devastating disorder aecting
around 35 million people worldwide [1]. Ten years ago,
there were 4.5 million persons with AD in the US population alone; the number has increased to 5.3 million people
in 2010, according to the Alzheimers Association [2]. It is
estimated there will be 13.2 million people with this
neurodegenerative disorder by 2050 [3].
Alzheimers disease is a primary, progressive neurological
disease, which is of unknown etiology in more than 90% of
the cases. Some characteristic neuropathological and neurochemical features lead to irreversible loss of neurons.
Owing to the nature of the primarily aected neuronal
circuits, the clinical hallmarks of AD are progressive
impairment in memory, judgment, decision making, orientation to physical surroundings, and distorted language.
This illness is the leading cause of dementia in older people
[2].

There currently is no cure for AD. A recent meta-analysis

of functional outcomes for commercially available acetylcholinesterase inhibitors and memantine in the treatment of
patients with AD, the only FDA-approved drugs for AD,
revealed only a modest trend favoring active treatment over
placebo [4, 5]. Anti-inammatory agents may reduce the
risk of developing AD [6], but, on the contrary, according
to results obtained from an elderly communitybased
cohort study, anti-inammatory agents could even be
dangerous for cognitive abilities [7]. It is also possible that
anti-inammatory drugs have no inuence at all with the
exemption of their well-known collateral eects [8, 9].
Vitamin E, estrogens, omega-3 fatty acids, and Ginkgo
biloba have been tested in dierent studies, and they yielded
contradictory results. And there is a long list of experimental therapies targeting dierent protagonists in the
pathology of AD, such as tau protein, amyloid-b (Ab
targets: formation, aggregation, or toxicity), Ab receptors
or N-methyl-D-aspartate (NMDA) antagonists, serotonin
167

Rosales-Corral et al.

Fig. 1. Major targets for Alzheimers

disease therapy.

receptors, loss of acetylcholine neurons, cholesterol, and

antiaging drugs (reviewed in [10]; Fig. 1).
Likewise, there is insucient clinical evidence to support
the eectiveness of melatonin by itself in managing the
cognitive and noncognitive sequelae of people with dementia [11]. However, there are molecular and physiological
bases that are worth analyzing, because melatonin may
have an eective inuence on several of the abovementioned AD protagonists and the most prominent
hypotheses to explain the cause of this disease, as reviewed
below. There is also a growing body of evidence indicating
the potential role of melatonin as an eective adjuvant in
AD management [1217]. On the contrary, there is one
report indicating essentially negative results after using
melatonin in patients with AD [18]. Even worse, there is a
single recent publication which claims that melatonin may
aggravate this neurodegenerative disorder [19].
The authors of the current review declare no conict of
interest related to this paper or nancial relationships with
commercial entities. The aim is to put together evidence on
melatonins role in the best-known hypotheses that currently attempt to explain AD pathogenic mechanisms,
starting with the fact that AD-related changes begin at the
age when melatonin levels fall signicantly. However, it is
also clear from the beginning that more than 100 yr after
the rst clinical report of a case of AD, there is not yet a
satisfactory hypothesis or a model capable of explaining or
reproducing the pathogenic mechanisms of this devastating
disease. Thus, all the proposed treatments for AD are
groping for optimal experimental outcomes in regard to
obviously incomplete hypotheses. This incompleteness may
explain, at least in part, how dierent models yield widely
dierent results. For example, long-term oral administration of melatonin in an amyloid precursor protein
(APP) + PS1 double transgenic mice model of AD protects against cognitive decits and markers of neurodegeneration [20], while it fails to protect animals expressing
the Swedish AD mutant gene (Tg2576 mice) exposed to
aluminum [21].
168

Melatonin levels in AD
Cerebral spinal uid (CSF) melatonin levels are reportedly
signicantly decreased in aged individuals with early
neuropathological AD-related changes in the temporal
cortex [22]. In aged patients, melatonin levels in CSF have
been found to be one-half those in young control subjects,
but in patients with AD, the CSF melatonin levels are only
one-fth those in young subjects [23]. In fact, it is possible
to replicate hippocampal CA1 and CA3 pyramidal neuron
loss in rats by merely removing the pineal gland (which
lowers melatonin levels) with this eect being reversed by
melatonin replacement in the drinking water [24]. Also,
constant light exposure, which decreases serum melatonin,
is enough to cause Alzheimer-like damage, such as memory
decits, tau hyperphosphorylation at multiple sites, activation of glycogen synthase kinase-3 and protein kinase A, as
well as suppression of protein phosphatase-1 and prominent oxidative stress [25].

Melatonin, mechanisms of action

Melatonin is derived from the aminoacid tryptophan in a
multistep process involving the synthesis of serotonin,
which is subsequently N-acetylated and O-methylated [26].
Melatonin is 5-methoxy-N-acetyltryptamine produced by
the functional elements of the pineal gland; once released, it
acts both as an endocrine product and as an antioxidant.
Several precursors of melatonin including tryptophan and
serotonin are reduced by aging, and their reduction may be
linked to AD appearance [27, 28] (Fig. 2). Tryptophan
deciency is related to an accelerated degradation attributed, as reviewed below, to homocysteine, a risk factor for
dementia and AD [29]. Serotonin deciency, on the other
hand, is linked to severe psychiatric symptoms in AD [28],
although serotonin dysfunction may appear long before
psychiatric symptoms; these symptoms are associated with
altered brain serotonin transporter and glucose metabolism
as identied using in vivo molecular imaging [30].

Alzheimers disease and melatonin

Fig. 2. Melatonin and its precursors,

tryptophan and serotonin (*), appear
reduced in aging, which is particularly
signicant in Alzheimers disease brain.

Besides the pineal gland, melatonin is also presumably

produced in gastrointestinal tract, airway epithelium, pancreas, adrenal glands, thyroid gland, thymus, urogenital
tract, placenta, and other organs [31]. Even nonendocrine
cells, such as mast cells, natural killer cells, eosinophilic
leukocytes, platelets, and endothelial cells, may produce
melatonin [32]; this wide synthesis underlines its diverse
physiological activities: from the control of biological
rhythms [33, 34], metabolism of free radicals [3539],
immune responsiveness [4042], monitoring of mood and
sleep [4345], cell proliferation and dierentiation [46, 47],
and control of seasonal reproduction [48, 49]. Importantly,
melatonin production declines with age [5053] because of
dysfunction of the sympathetic regulation of pineal melatonin synthesis by the suprachiasmatic nucleus (SCN), a
condition probably linked to early AD stages, once that the
reactivation of the circadian system using light therapy and
melatonin has shown promising positive results [54].
Firmly established as the key mediator controlling
circadian rhythms [33, 34, 55], it has been discovered that
melatonin, a small, lipophilic molecule, also had the
capacity to directly scavenge the hydroxyl radical (OH)
[56, 57]. Almost immediately, a link between melatonins
hydroxyl radical-scavenging activity and aging was envisioned [58] as well as realizing that aging and Ab-induced
oxidative stress play a key role in AD as well.

Currently, melatonin is recognized both as a free radical

scavenger and as an antioxidant [59]. Thanks to its electronrich aromatic indole ring, melatonin directly donates an
electron to free radicals at a potential of 715 mV and avoids
redox recycling (reviewed in [60]), while it scavenges, with
varying degrees of eciency, the hydroxyl radical [56, 60
64], hydrogen peroxide [65], hypochlorous acid [66], singlet
oxygen [67], superoxide anion radical [68], nitric oxide [69],
and the peroxynitrite anion [70] (Fig. 3). Radicals may also
be added in the C3 amide side chain of melatonin, which
possesses an NC=O functional group [71]. The rate
constant for the scavenging of the OH by melatonin is
calculated to be on the order of 2.7 1010/M/s [72].
The free radical-scavenging capacity of melatonin also
extends to its secondary, tertiary, and quaternary metabolites in a free radical-scavenging cascade that prolongs
its useful life [7375]. Thus, the interaction of melatonin
with free radicals produces the oxidative pyrrole-ring
cleavage, giving N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and this substituted kynuramine may
donate two electrons at dierent potentials (456 and
668 mV, respectively) to function as a reductive molecule
capable to destroy reactive species and to protect macromolecules against oxidative damage [76]. Thus, via the
AFMK pathway, a single melatonin molecule may scavenge up to 10 reactive oxygen and reactive nitrogen species

Fig. 3. Major oxidant pathways and the

role of melatonin as an antioxidant
(dashed blue arrows), promoting the
activity of antioxidant enzymes. Derived
from metabolic activity, particularly
from mitochondria in aging, melatonin
plays an important role as a free radical
scavenger (blue balloons).

169

Rosales-Corral et al.
(ROS/RNS) [73]. Further AFMK deformylation by the
action of arylamineformamidase or hemoperoxidase enzymes produces N1-acetyl-5-methoxykynuramine (AMK)
[77], which, in addition to its ability to react with various
oxidizing and nitrosating free radical species, particularly
singlet oxygen and nitrogen species, also may destroy
carbonate and peroxyl radicals (reviewed in [78]) and
function as an antioxidant [79]. AFMK and AMK metabolism may lead to other oxidation products, such as 3indolinone, cinnolinone, and quinazoline compounds, for
which no specic functions have been identied to date [78].
Interestingly, the parallel orientation of b-sheets, such as
tau and Ab laments, generates channels extending along
the length of the lament to which aromatic small molecules such as indolinones can bind via pp interactions,
stacked arrangement of aromatic molecules [80]. Using
uorescence spectroscopy, atomic force microscopy, and
electron microscopy to screen 29 indole derivatives, Cohen
et al. [81] identied three potent inhibitors of amyloid bril
formation and cytotoxicity, and the indole-3-carbinol was
among them. The interaction of melatonin with Ab will be
reviewed below. Additionally, the 3-substituted indolinones
have been identied as kinase inhibitors [82], which could
be related to the anti-inammatory actions of melatonin
and its metabolites [83].
Melatonin may also prevent abnormal elevation of
reactive nitrogen species, stimulate other antioxidant systems, and/or inhibit some pro-oxidant enzymes; these
indirect actions of melatonin contribute to its potent
antioxidant activity [8486]. An evaluation in human

diabetic skin broblasts demonstrated that melatonin

increases the activity of superoxide dismutase (SOD),
catalase (CAT), and glutathione peroxidase (GPx) and
the level of glutathione (GSH) [87] (Fig. 3). Similar results
have been obtained in fetal rat brain [88], in experimental
brain trauma [89], as well as in cultured dopaminergic cells
[90] and, of course, in AD transgenic mouse brain [91, 92].
These observations allow for the conclusion that melatonin
exerts an antioxidant action by increasing the mRNA levels
of the antioxidant enzymes SOD, CAT, and the GSH
system, but it may depend somewhat on the model system
investigated.
Finally, melatonin exhibits a lower-anity binding site to
a cytosolic quinine oxidoreductase 2 or QR2, also known as
MT3 (reviewed in [93]). This enzyme, as any other quinone,
has the ability to transform its substrates into more highly
reactive compounds that are able to cause cellular damage.
Once melatonin binds to its large active site, the enzyme
produces fewer hydrogen bonds and hydrophobic contacts,
which diminishes their reactivity [94] (Fig. 4).
Melatonins best-known receptors, MT1 and MT2, are
transmembrane G-protein-coupled heterodimers whose
signaling pathways lead to downstream eects on Ca2+
channels, Ca2+ signaling, and changes in MAP and ERK
kinases and/or PI3K/Akt pathways [95] (Fig. 4). This
means a broad spectrum of possibilities for melatonin is
one factor that gives the indoleamine a pleiotropic nature
[96, 97].
Once again, it is worth noting that the pathogenic
mechanisms in AD are not well understood, and there are

Fig. 4. Receptor-mediated or acting directly on its substrates, melatonin exhibits a broad diversity of eects to reduce neurodegenerative
changes in the central nervous system. It is a pleiotropic indoleamine, actually. All the protagonists in neurodegenerative diseases express
melatonin receptors; when and how cells or their molecular eectors become activated or inhibited according to the expression of their
melatonin receptors remains unclear. The scheme shows some of the published observations to date, all related to central nervous system
and/or neurodegeneration. Thanks to its ability to transfer electrons, melatonin may repair damaged biomolecules derived from DNA
oxidation, such as guanosine. LTP, long-term potentiation; MT, melatonin receptor (G-protein-coupled receptors); CaM, calmodulin; CRT,
calreticulin; APP, amyloid b precursor protein; 5-LOX, 5-lipoxygenase; COX-2, cyclooxygenase; iNOS, inducible nitric oxide synthase;
PLA2, phospholipase A2.

170

Alzheimers disease and melatonin

many hypotheses regarding this major cause of dementia.
The three major hypotheses as well as their derivatives will
be the common thread throughout this review. What has
been published regarding melatonin and its potential role in
each proposed mechanism will be added herein, where
appropriate.

Pathogeny of AD
There is a failure of the intercommunication between
neuronal circuits in Alzheimers disease resulting from
synaptic loss and the destruction of neurons. As a consequence, working memory is not transferred through the
hippocampus to long-term memory circuits. The disconnection progresses over time and aects some other
functions in addition to memory, so that behavior, executive functioning, judgment, movement coordination, and
pattern recognition may become eventually aected.
Three major hypotheses have been primarily explored in
an attempt to explain AD: (i) cholinergic hypothesis, (ii)
amyloid cascade hypothesis, and (iii) mitochondrial cascade
hypothesis. Even though the amyloid cascade is the most
extended hypothesis [98], the pathogenic role for Ab is
under debate because of reports showing a poor relationship between Ab accumulation and cell death in the brain,
in addition to other results demonstrating a weak correlation between Ab and cognitive decline [99]. Furthermore,
people with Ab deposits do not necessarily suer AD [100].
Even more importantly, there are some published data
demonstrating that Ab may be protective in brain disease
[101, 102]. Thus, the pathogenic role of Ab in AD deserves
further scrutiny because all of the hypotheses mentioned
include a pathological role of Ab in AD.

Amyloid-b processing
Although far from conclusive, Ab is the most studied factor
related to pathogenic mechanisms of AD. Ab is derived
from the catalytic cleavage of an integral membrane
protein, the APP, a ubiquitously expressed type I transmembrane protein whose primary function is not well
known. This is the rst obstacle in Alzheimers research,
actually. It is known that the lack of APP in hippocampal
neurons enhances neuritic growth, which inuences only
the synapse number at an early age but not in adult animals
[103]. The conserved APP intracellular domain, genetically
uncoupled from APP processing and Ab pathogenesis, has
a key role in survival, proper high-anity choline transporter (ChT) targeting, and neuromuscular synapse development [104]. ChT is responsible for choline uptake from
the synaptic cleft, a rate-limiting step in acetylcholine
synthesis [105]. An extensive review [106] tackles in detail
the possible role of APP in synaptic transmission and
neural plasticity, with its respective implications for learning and memory.
Closely associated with lipid rafts in membranes, composed mostly of sphingolipids and cholesterol, the enzymes
in charge of APP cleavage are proteases generating soluble
isoforms of membrane proteins, a process rst related to
the secretion of angiotensin-converting enzyme in the
kidney [107]. Thus, the APP chain of 695, 751, or 770

amino acids may suer consecutive cleavage events. The

large extramembranous N-terminal region may undergo
proteolysis by the a-secretase that cleaves the molecule
between Lys687 and Leu688, releasing a large (105
125 kDa), soluble ectodomain known as sAPPa [108]. This
sAPPa carries a portion of the Ab sequence [109] that
normally includes 28 amino acids of the extracellular and
1215 residues of the membrane-spanning region of APP;
thus, the subsequent formation of amyloidogenic peptides
may be precluded. This a-secretase may be modulated by
metal ions and metalloprotease inhibitors and three related
disintegrin and metalloprotease enzymes, ADAM9 [110],
ADAM10 [108], and ADAM17 [111], which seem to exert
an a-secretase activity. It has been speculated that the
activation of these proteases, representing a nonamyloidogenic pathway, may oer a therapeutic method in AD [112,
113]. As a matter of fact, it is remarkable that levels of asecretase ADAM-10 and sAPPa are reduced in the CSF of
patients with AD compared to that of controls [114].
The amyloidogenic pathway is established by the concerted action of two secretases, the b-secretase, which
cleaves the APP-N terminus, and the c-secretase, which
cleaves the APP-C terminus in the secondary transmembrane region. b-secretase is an aspartyl protease of 501
amino acids with two aspartic protease active site motifs,
which is known as the b-site APP cleaving enzyme I or
BACE-1 [115] and considered a prime drug target for
lowering cerebral Ab levels in the treatment for and/or
prevention of AD. It is the initiating and rate-limiting
enzyme in Ab generation. BACE-1 activity on APP is
related to the accessibility of APP within a lipid raft zone of
the membrane [116, 117]. Once APP escapes from processing at the a-site, it is cleaved at the luminal domain,
resulting in a 12 COOH-terminal fragment (C99), which
remains membrane bound, and the soluble APPb NH2terminal fragment (sAPPb) [118, 119]. Then, C99 is cleaved
from the membrane by the c-secretase, a multisubunit
protease complex composed of a presenilin catalytic subunit in addition to nicastrin, the anterior pharynx-defective
1 (APH-1), and the presenilin enhancer 2 (PEN-2) [120,
121]. Binding of cholesterol to C99 appears to favor the
amyloidogenic pathway in cells by promoting localization
of C99 in lipid rafts [122]. The resultant peptide of 3943
amino acid residues, Ab, is delivered to the extracellular
milieu where it forms insoluble aggregates and becomes the
major component of senile plaques. Ab140 and Ab142 are
the most common Ab isoforms. Aberrant Ab142 accumulation within distal neurites and synapses is directly
associated with subcellular pathology and neurotransmitters [123125], while Ab140 is the predominant form of the
Ab peptides but less prone to form brils [126]. As a
consequence of re-internalization from the extracellular
space [127, 128] or directly by the cleavage of APP in
endosomes generated from the endoplasmic reticulum (ER)
or the Golgi apparatus, Ab peptide accumulation also
occurs inside neurons leading to tracking problems, early
axonopathy, synaptic loss, and neuron death [129131].
What determines which enzyme will gain access to APP,
thus determining the course of events? There are clues
indicating that cholesterol in lipid rafts directly binds the
C-terminal transmembrane domain of APP, and this
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Rosales-Corral et al.

Fig. 5. Several routes to prevent the formation of Ab neurotoxic aggregates are used by melatonin. It directly intervenes, aecting the
stability of amyloid b-sheets by disrupting Asp) -His+ salt bridges or aecting the synthesis and maturation of APP, where its ability to
suppress cAMP activity may have a role, because of the cAMP-responsive regions on the APP promoter gene. However, its indirect actions
are signicant as well because melatonin may reduce the activity of GSK3 required for the amyloidogenic APP processing, by activating
and/or enhancing the activity of PKC, or by inducing Akt. Both PKC and Akt may turn o GSK-3 through phosphorylation. COX-2,
related to APP synthesis in astrocytes, is controlled by melatonin and its metabolites. Finally, melatonin has a key role in cholesterol and
fatty acid distribution in membranes, as reviewed later. This is important because, as illustrated, amyloidogenic APP processing seems to be
favored by cholesterol/sphingomyelin-enriched lipid rafts. APP, amyloid precursor protein; bs, b secretase; cs, c-secretase; Ab, amyloid b;
MT, melatonin receptors; PLC, phospholipase C; DAG, diacyl-glycerol; PKC, protein kinase C; PI3K, phosphatidylinositol-3-kinase; Akt,
a serine/threonine protein kinase; PKA, cAMP-dependent protein kinase.

interaction may be a determinant in favor of the amyloidogenic pathway [122] (Fig. 5). Cholesterol decreases the
secretion of soluble amyloid precursor protein (sAPP) by
interfering with APP maturation and inhibiting glycosylation in the protein secretory pathway, in such a manner that
APP cannot be cleaved by a-secretase [132]. Processing APP
at the b-site also requires proper orientation to be accessed
by BACE-1 [133], which in turn localizes largely within
cholesterol-rich lipid rafts [117, 134]. It is proposed that
APP is actually a cholesterol sensor [117]. The AD brain
shows signicant cholesterol retention and high b- and csecretase activities as compared to age-matched nondemented controls, while cholesterol depletion may be associated with reduced cellular cholesterol, b-secretase activity,
and Ab secretion [116].
Another factor inuencing the access to APP in cell
membranes seems to be insulin, a signicant association
that links AD to diabetes mellitus. Insulin accelerates APP
tracking from the trans-Golgi network to the plasma
membrane [135], while the insulin-degrading enzyme (IDE)
degrades not only insulin but also Ab and the intracellular
domain of APP [135, 136]. Thus, insulin reduces intracellular levels of amyloid and increases amyloid secretion in a
process that probably involves the activation of the MAPK
cascade [137], although it might also use the phosphatidyl
inositol 3 kinase (PI3K)-pathway to release sAPP, the
172

nonamyloidogenic secreted form of APP [138]. Importantly, this insulinPI3K pathway locates and halts glycogen synthase kinase-3 (GSK-3) to promote glucose storage
as glycogen, as part of intermediary metabolism. However,
GSK-3 plays another role. Its a-isoform may interact
directly with presenilins within the c-secretase complex, and
it is required for the amyloidogenic APP processing. This is
the reason why GSK-3 has become a target for the
treatment for AD [139]. Insulin deciency in brain leads
to enhancement of GSK3a/b activation, increases cerebral
amyloidosis, and exacerbates behavioral decits, as demonstrated in APP/PS1 transgenic mouse model of AD by
impairing insulin downstream GSK3 and JNK pathways
[140].
Not only brillar Ab but a variety of Ab oligomers may
cause cellular damage. Soluble oligomers, referred to as
amorphous aggregates, micelles, protobrils, prebrillar
aggregates, amyloid b-derived diusible legends (ADDLs),
Ab*56, globulomers, amylospheroids, toxic soluble Ab,
paranuclei, and annular protobrils [141], appear within
neuronal processes and synapses rather than within the
extracellular space. They are neurotoxic rather than amyloid brils found in amyloid plaques [142] and may inhibit
critical neuronal functions including long-term potentiation
[143], a classic experimental paradigm for memory and
synaptic plasticity [143, 144]. Even more, as a consequence

Alzheimers disease and melatonin

of inhibition of the proteasome function, soluble oligomers
may cause cell death [124]. Extracellular soluble Ab species,
on the other hand, are deposited around neuronal cell
bodies and may interact with the lipid bilayer within
dendritic arbors at discrete points, appearing co-localized
with the postsynaptic density protein 95 (PSD-95) [145],
which is related to synapse stabilization and plasticity [146].

Melatonins role on amyloid-b processing

There are some clues indicating an interaction between
melatonin and Ab. By using a thioavin T (Th T)
uorescence assay, which measures the binding abilities of
dierent compounds with Ab, it is possible to demonstrate
that melatonin directly interacts with Ab and prevents its
aggregation [147]. This fact has been well known since 1997,
when it was documented using circular dichroism, electron
microscopy, and nuclear magnetic resonance spectroscopy
[148]. This phenomenon is not related to the antioxidant
properties of melatonin [149] and involves the disruption of
the His+-Asp) salt bridges in Ab peptide, which are
determinants for the formation and stabilization of b-sheet
structures [150]. Thus, 24 hr after the incubation with
melatonin, Pappolla et al. [148] showed that original
b-sheet content of Ab was signicantly diminished in
opposition to the increase in b-sheet content when Ab
was incubated alone (Fig. 5).
A direct interaction between the 5-methoxy group on
melatonin and His-13 of Ab may occur as well. This
eventuality may be attributed to the higher binding energies
in the 5-methoxyindole group, according to single-point
energy calculations [151]. Further investigations by electrospray ionization mass spectrometry (ESI-MS), the hydrophobic nature of Ab, and melatonin interaction has been
unveiled, and the proteolytic assessment suggests that the
interaction takes place on the 2940 Ab-peptide segment
[152]. As compared with some other antiamyloidogenic
agents, such as daunomycin or the melatonin analogue 3indolepropionic acid, melatonin exhibits a moderate degree
of inhibition of aggregation, as evaluated by ESI-MS [153].
It is also possible that melatonin could regulate the
synthesis and full maturation of APP, as it was demonstrated in melatonin-treated PC12 cells, which responded
by decreasing its mRNA encoding b-APP. According to
Lahiri and Song [154, 155], melatonin accomplishes this
while potentiating the nerve growth factormediated
dierentiation.
Because APP gene promoter contains c-AMP-responsive
regions, it is possible that c-AMP signaling pathways may
induce APP synthesis, and this eventuality could be a link
between neuroinammation and neurodegeneration, as
explored by Lee et al. [156]. They found that prostaglandins
produced by brain injury or inammation increases cAMP
formation and stimulates overexpression of APP mRNA
and holoprotein in primary cultures of cortical astrocytes.
On the other hand, the relationship between melatonin or
its metabolites and neuroinammation relies importantly
on its ability to inhibit prostaglandins by interfering with
the COX-2/PGE pathway [157], which implies the participation of cAMP as a second messenger. In fact, acting
through its membrane receptors, melatonin may block

cAMP production, protecting white matter against a

neonatal excitotoxic challenge. This neuroprotective eect
may be prevented by luzindole, a well-known membrane
melatonin receptor antagonist, or by forskolin, an adenylate cyclase activator [158]. Thus, in a receptor-mediated
manner and by inhibiting adenylyl cyclase, melatonin may
impair cAMP signaling, which is probably involved in the
activation of the APP gene promoter. Therefore, melatonin
could interfere with APP synthesis (Fig. 5).
Acting through its MT2 receptor, melatonin stimulates
phospholipase C (PLC) and, via diacylglycerol (DAG),
activates protein kinase C (PKC) [159], which in turn
phosphorylates and inactivates GSK-3, whose participation
in APP synthesis is key, as mentioned before. However,
PKC is also capable to directly promote a-secretasemediated cleavage of APP favoring the nonamyloidogenic
pathway [160]. Thus, by activating PKC, melatonin might
impair Ab overproduction (Fig. 5). Moreover, acting
through its membrane receptors, melatonin uses a PI3Kdependent pathway to activate Akt, a serine/threonine
protein kinase, which, besides participating in multiple
survival pathways, phosphorylates and inactivates GSK-3
[161]. PI3K/Akt is the same pathway employed by insulin
and by the insulin growth factor-1 receptor (IGF-1R) to
interrupt GSK-3b activity under oxidative conditions [162]
(Fig. 5).
Because the JNK pathway also could be involved in
GSK-3 activation [140], we speculate that melatonin, which
prevents JNK activation under oxidative stress conditions
[163], may also employ this mechanism to prevent the
activation of GSK-3. It is also feasible that melatonin, in its
role as antioxidant, might enhance PKC anti-GSK3 activity
by avoiding PKC inactivation. This may occur because
PKC is redox sensitive and may be S-glutathiolated and
inactivated during oxidative stress in the brain. Oxidative
stress is a well-documented phenomenon in Alzheimers
[164].
Stopping GSK-3 activity could be important not only in
interrupting APP synthesis but also to reduce tau hyperphosphorylation, because GSK-3 phosphorylates tau [165,
166]. It is worth remembering that the microtubule-associated protein tau is the other key protagonist in AD
pathology, being responsible, once hyperphosphorylated,
for paired helical lament (PHF) formation.
An indirect interaction between melatonin and Ab
processing has been also proposed involving the hypoxiainducible factor-1 (HIF-1), which upregulates BACE-1,
facilitating the generation of cytotoxic Ab peptide [167]. In
fact, at a pharmacological dose, melatonin may prevent the
generation of Ab peptides by reducing both the BACE-1
protein and its mRNA, as demonstrated in a rat model
employed to evaluate the eect of chronic intermittent
hypoxia (CIH) on the Ab generation in the hippocampus.
Being a redox-sensitive transcription factor, HIF-1 is
susceptible to melatonin redox modulation [164, 168] and,
via this indirect manner, melatonin might prevent the
formation of Ab. HIF-1 has been observed to be abundant
in AD microvessels where it regulates proinammatory
gene expression [169]. On the contrary, it is also known that
the accumulation of Ab by using a nonhypoxic mechanism
may induce the accumulation and nuclear translocation of
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Rosales-Corral et al.
HIF-1, which in turn mediates a neuroprotective response,
presumably by regulating glucose metabolism [170]. HIF-1
has a half-life of approximately 5 min in normoxic conditions and less than a minute under hypoxic conditions.
Thus, the role of melatonin in these HIF-1 dependent
mechanisms is currently only a matter of speculation.
Conformational changes in Ab occur in minutes after
addition of melatonin. In fact, the ability of melatonin to
induce conformational changes in Ab has been used to
investigate the conformation and topology of Ab peptides
interacting with peptide-tethered planar lipid bilayers [171,
172]. Similarly, it has been also demonstrated that lipid
composition of membrane bilayers plays a dominant role in
mediating conformational changes and in AD pathogeny,
as reviewed below.
Levels of Ab aggregates in the brain were reduced by
melatonin in aging mice [173], and in 8-month-old APP 695
transgenic [174] mice or in APP + PS1 double-transgenic
mice. The latter were supplemented with melatonin from 2
to 2.5 months to age 7.5 months [20]. However, in old,
amyloid plaquebearing Tg2576 mice, which started melatonin treatment as late as 14 months of age (5 months
later from the onset of the pathology [175]), melatonin
failed to reproduce its antiamyloid eects (it seems to even
fail to prevent oxidative stress [176]).
The melatonin/Ab interaction could be an inconvenience
according to the bioocculant hypothesis. Even though
the investigation related to inhibitors of Ab aggregation as
a real promise for many investigators [177], blocking or
inhibiting Ab could be a mistake owing to the soluble forms
of this peptide, according to this hypothesis. This is because
Ab could have a primordial function: binding to unwanted
solutes in the extracellular uid, which then precipitates to
build deposits or aggregates. Thus, Ab plaques would be an
ecient means of presenting neurotoxins to phagocytes
[178].
Extracellular Ab may suppress synaptic plasticity or
inhibit long-term potentiation (LTP) [179]. There is, in fact,
an odds ratio homocysteine/AD of 4.5 for histopathologically conrmed AD in a casecontrol study [180], which
also demonstrated that patients with AD and high homocysteine levels showed a more rapid progression over the
following 3 yr. Even more so, high homocysteine levels,
considered a risk factor for dementia and AD [29], are
related to apoptosis [181]. This methionine derivative has
the ability to induce proapoptotic caspases (caspase 3 and
caspase 9), DNA fragmentation, and the Bcl-2associated
X protein (Bax) while reducing the antiapoptotic Bcl-2
protein; these eects may be inhibited in the presence of
melatonin [182].

Cholinergic hypothesis
The cholinergic hypothesis asserts that degeneration of
cholinergic neurons in the basal forebrain and the associated loss of cholinergic neurotransmission in the cerebral
cortex cause deterioration in cognitive function as seen in
patients with AD [183, 184]. This theory was introduced in
1971 when it was demonstrated that cholinergic synapses
were modied as a result of learning and that loss of
sensitivity to acetylcholine was related to forgetfulness
174

[140]. Years later by damaging cholinergic input to the

neocortex or hippocampus from the basal forebrain, it was
possible to reproduce a memory impairment as observed in
AD [141]. Based on this old hypothesis, increasing the
synaptic levels of acetylcholine (Ach) with the use of
acetylcholinesterase (AchE) inhibitors has been employed
as a treatment and is considered the standard of care for the
treatment for mild-to-moderate AD; meanwhile, the search
for new AchE inhibitors continues [185]. However,
although it remains as a rational approach, nowadays the
real ecacy of this treatment is under debate [142].
Both Ab and oxidative stress may reduce Ach synthesis
by reducing choline acetyltransferase activity [186, 187].
However, acetylcholine depletion in the AD brain is also
related to free cytosolic ionic calcium and oxidative stress.
It is well known that Ab induces elevations of intracellular
free Ca2+ by increasing calcium entry through L-type
voltage-dependent calcium channels [188], and AchE
release is a Ca2+-dependent phenomenon [189]. In this
manner, Ab may elevate AChE activity, as demonstrated in
P19 cells [190]. Furthermore, oxidative stress, which is a key
protagonist in AD, also plays a role in the enhancement of
acetylcholinesterase activity induced by Ab peptide [191].

Melatonins role on the cholinergic

hypothesis
The Ab-induced AchE activity may be signicantly reduced
by melatonin, protecting mice from Ab-induced acetylcholine degradation [147]. Even in LPS injected mice, which
exhibit AchE overactivity, melatonin inhibits this eect as
demonstrated in the neocortical and hippocampal regions
in vivo [192].
Ab selectively interacts with the potentially neurotoxic
NMDA receptor via a postsynaptic site [193], leading to
dysregulation of Ca2+, which is explained because an
intense stimulation of NMDA-type glutamate receptors
results in a sustained elevation of cytosolic free calcium
([Ca2+]c) and its consequential dysregulation [194]. The
mechanism of AchE control may be related to the stabilization of Ca2+ levels, because it seems that the increase in
AChE expression around amyloid plaques is a consequence
of a disturbance in calcium homeostasis; in fact, intracellular calcium mobilization upregulates AChE expression by
modulating promoter activity and mRNA stability and, on
the contrary, chelation of intracellular Ca2+ may inhibit
acetylcholinesterase expression [195]. Thus, by controlling
[Ca2+]c, it is possible to control AchE activity. Melatonin
controls Ca2+ inux through dierent pathways, and by
these means, it could control acetylcholinesterase expression as reviewed below. Hence, melatonin is important as
an acetylcholinesterase and butyrylcholinesterase inhibitor,
especially the cyclic 3-hydroxymelatonin analogues, which
exhibit structural similarity to cholinesterase inhibitor
drugs [196, 197] (Fig. 6). Melatonin, like insulin and the
anticholinesterase drug, donepezil, exhibits an antiamnesic
eect in amnesic mice mediated by enhancement of
cholinergic activity at the expense of decreasing AChE
activity [198].
Considering that oxidative stress and particularly peroxynitrite (ONOO)) overproduction is signicant in AD

Alzheimers disease and melatonin

levels as observed in the transgenic animals [174]. It is
possible to nd ChAT oxidatively modied by the lipid
peroxidation product, 4-hydroxy-2-nonenal (HNE) [203], a
diusible electrophile that covalently binds to proteins via
Michael addition to Cys, His, and Lys residues [164, 204,
205]. Thus, owing to its free radical-scavenging activity as
well as its indirect antioxidant actions, melatonin may
reduce ChAT nitrosylation and/or oxidation [186] (Fig. 6).
However, in rats infused intracerebroventricularly with
amyloid-beta for 14 days, where ChAT activity was significantly reduced, melatonin was unable to restore the
activity of this enzyme [205].

Oxidative stress and neuroinflammation in

the pathology of AD

Fig. 6. Melatonin may have a role as an acetylcholine enhancer by

blocking the Ca2+-dependent release of anticholinesterase enzyme
(red cross #1) or allowing the proper reentry of choline (red cross
#2) by avoiding ChT oxidation. It is possible that melatonin restores ChAT activity under oxidative stress conditions (red cross
#3) as observed in APP transgenic mice. However, the role of
melatonin in cholinergic hypothesis remains to be claried because
oxidative stress along with calcium dysregulation, as observed in
chronic cellular stress, is relevant in acetylcholine expression and its
metabolism as well as Ach receptor activity (red cross #4). Mit,
mitochondria; ER, endoplasmic reticulum; ChAT, choline acetyl
transferase; Ach, acetylcholine; ChT, choline transporter; AchE,
acetylcholinesterase; AchR, acetylcholine receptor.

brain, where the latter mediates neurotoxicity of Ab [199], it

is possible that S-nitrosylation of metabolic Ach intermediaries has a signicant role. Among the multiple targets of
OONO) in AD brain, choline acetyltransferase (ChAT)
may be a good candidate. ChAT, whose activity has been
shown to decrease in the AD brain [200], may undergo
S-nitrosylation followed by lysis and oligomerization, as
demonstrated in cholinergic nerve endings and synaptic
vesicles from Torpedo marmorata electroneurons [186].
Even though the mechanism is not fully understood, the
high-anity ChT, which provides choline for acetylcholine
synthesis in neurons, seems to be regulated by OONO) as
well [201]. Thus, we speculate that melatonin may promote
choline transport [200, 202] (Fig. 6).
There are some other factors also involving melatonin in
the cholinergic hypothesis even though the mechanism is
not fully understood. For example, ChAT, which binds
acetyl coenzyme A to choline in Ach synthesis, has been
found decreased in the frontal cortex and hippocampus of
APP 695 transgenic mouse model of AD, and melatonin,
chronically administered for 4 months, restored ChAT

It is well known that the accumulation of Ab in plaques as

well as Ab oligomers may produce sequential inammatory/oxidative events and excitotoxicity, causing neurodegeneration and cognitive impairment [206]. In one way or
another, all the proposed mechanisms for explaining AD
pathogenic mechanisms are connected to oxidative stress
and neuroinammation, widely known hallmarks not only
for AD but in general for all neurodegenerative diseases
and obviously linked to the amyloid cascade [207209].
Metabolic signs of oxidative stress in AD are always
evident in neocortex and hippocampus, related to alterations in synaptic density. In response to elevated brain
peroxide metabolism, AD brains show increased cerebral
glucose-6-phosphate dehydrogenase activity [210], which is
the rst and rate-limiting enzyme of the pentose phosphate
pathway, central to maintenance of the cytosolic pool of
NADPH and thus the cellular redox balance. Even the
brains of preclinical AD individuals, with normal antemortem neuropsychological test scores but abundant AD
pathology at autopsy, may exhibit increased levels of the
major product of lipid peroxidation, 4-hydroxynonenal,
and acrolein, a powerful marker of oxidative damage to
protein [211]. Inferior parietal lobule samples from early
AD patients compared to age-matched controls have been
examined for proteomic identication of nitrated brain
proteins that revealed signicant alterations in antioxidant
defense proteins and energy metabolism enzymes, with all
of them being directly or indirectly linked to AD pathology
[212].
Ab neurotoxic properties depend heavily on free radicals.
The overproduction of free radicals in the pathogeny of AD
may come from the microglial respiratory burst in response
to Ab-induced neuroinammatory events [213216]. The
microglial respiratory burst in AD may result from (i) the
interaction of Ab with specialized receptors, (ii) the
astrocyte/microglia intercommunication, or (iii) detection
of damage-associated molecular patterns (DAMPs)
through their corresponding receptors, leading to the
activation of the phagocytic nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (PHOX). The activation of the NADPH oxidase probably both in neurons and
in glia [217219] links redox control and neuroinammatory signaling pathways [220].
Ab causes microglial proliferation mediated by PHOX,
which is demonstrated by a marked translocation of the
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Rosales-Corral et al.
cytosolic factors p47phox and p67phox to the microglial
membrane in brains of patients with AD, and this is
correlated with proinammatory events, such as TNF-a
and IL-1b overproduction [221, 222]. The synergy between
oxidative and nitrosative stress plus neuroinammation
may increase the overproduction of OONO) by a
1,000,000-fold [223]. PHOX is a multicomponent enzyme
system composed of two integral membrane proteins,
p22phox and gp91phox, integrated as cytochrome b558,
three essential cytosolic components, p47phox, p67phox,
p40phox, and the above-mentioned GTPase Rac1, of the
Rho family of small G proteins. In general terms, the
complex begins its integration when the cytosolic p47phox
subunit becomes phosphorylated and transports the total
cytosolic components to the docking site where they
assemble to the avocytochrome b558 (reviewed in [224]).
GTP-bound Rac coordinates the translocation of the
p47phox/p67phox/p40phox complex and its dissociation
from GTP permits the subsequent inactivation of the

PHOX complex, a crucial step where SOD plays a key role

acting as a stabilizer of Rac [225]. Once integrated, PHOX
transfers electrons from NADPH to molecular oxygen
generating O
2 .
Because Ab induces oxidative stress that is related to
mitochondrial damage, a mechanism closely linked to
apoptosis is established [226229]. Reciprocally, oxidative
stress may induce intracellular accumulation of Ab,
enhancing the amyloidogenic pathway [226, 230, 231]
(Fig. 7).
Additionally, Ab142 may initiate free radical chain
reactions by itself. It has a critical methionine residue at
position 35, which is highly hydrophobic and possesses a
sulfur atom sensitive to oxidation (:S: O=S:
O=S=O) [231], or if the lone pair of electrons on the S
atom undergoes one-electron oxidation, it produces a
positively charged sulfuranyl radical (MetS+) [232]
(Fig. 7). In this manner, SO bonded MetS+ may initiate
free radical chain reactions with allylic H atoms on

Fig. 7. Ab plaques and oligomers are in the middle of a complex set of interactions among astrocytes, microglia, and neurons originating a
neuroinammatory response. This is linked to reactive oxygen species (ROS) and NOS overproduction (gray clouds) culminating in
oxidative stress, which in turn feeds back on neuroinammation. Organelle dysfunction, particularly mitochondria, adds more free radicals
and aggravates the situation. Even worse, oxidative stress and Ab are interdependent phenomena; thus, the more the oxidation, the
more the amyloid accumulation. Newly formed Ab contributes to more neuroinammation and oxidative stress, closing the vicious cycle. In
fact, Ab can be an oxidant by itself, as shown. During inammatory and oxidative stress, communication between cellular protagonists is
importantly mediated by calcium waves (blue waves) apart from cytokines. Melatonin (green) and its major metabolites AFMK and
AMK play key roles by scavenging free radicals directly, while they enhance endogenous antioxidant systems, as shown in Fig. 3. AMK is
relevant particularly in mitochondria, where it takes ETC components as electron donors or acceptors. Going further, melatonin and its
metabolites have a role in neuroinammation by regulating both proinammatory signals and oxidative stress mediators, such as COX2
and iNOS by avoiding NF-jB full integration. ctk, cytokines; Ab, amyloid-beta; AFMK, N1-acetyl-N2-formyl-5-methoxykynuramine;
AMK, N1-acetyl-5-methoxykynuramine; 3-OHM, cyclic 3-hydroxymelatonin; ETC, electron transport chain; NF-jB, nuclear factor kappa
B; COX-2, cyclooxygenase 2; iNOS, inducible nitric oxide synthase; PGE2, prostaglandin E2.

176

Alzheimers disease and melatonin

unsaturated acyl chains of lipids making the lipid hydroperoxide and propagating the chain reaction [233].
Ab can also directly trap molecular oxygen, reducing it to
H2O2 in the presence of iron (Fenton reaction), as it has
been demonstrated by spectrochemistry in AD brain [234].
Fe2+ ions are generated via a redox cycling of iron (Fe2+
M Fe3+), and in the presence of a metal chelator, such as
clioquinol, this Ab neurotoxicity is reduced [235]. The
matter is relevant because signicant alterations in Cu, Zn,
and Fe have been found in AD brain in those areas showing
severe histopathologic alterations [236, 237]. In general,
drugs that prevent oxidative stress include antioxidants,
modiers of the enzymes involved in ROS generation and
metabolism, metal-chelating agents and agents, such as
anti-inammatory drugs, that can remove the stimulus for
ROS generation.
H2O2 is a well-known uncoupler of the mitochondrial
respiratory activity, producing a concentration-dependent
inhibition of state 3 (ADP-stimulated) respiration and
reducing substantially the ADP:O ratio [238]. An evaluation of electron transport chain complexes and Krebs cycle
enzymes revealed that a-ketoglutarate dehydrogenase, succinate dehydrogenase, and aconitase are susceptible to
H2O2 inactivation, which is a reversible process [239].
Under normal conditions, excessive ROS are neutralized
by the action of endogenous and exogenous antioxidant
defense systems. In addition to the above-mentioned
oxidant-generating properties, Ab may bind the peroxidase
enzyme, CAT with high anity, inhibiting H2O2 breakdown [240] and thus worsening redox conditions. However,
all the antioxidant mechanisms play roles in the AD brain.
Thus, the overexpression of superoxide dismutase-2 (SOD2), which is localized to mitochondria, scavenges hippocampal superoxide and prevents memory decits in Tg2576
AD mice [241], which carry both mutant APP and
presenilin 1 transgenes [242]. In another AD mouse model,
3xTg-AD, there are signicant rises in the activities of SOD
and GPx, compared with the controls, whereas levels of
reduced GSH are signicantly decreased with a concomitant rise in oxidized glutathione (GSSG). This set of events
implicates a high oxidative state and depletion of proton
donors [243]. The 3xTg-AD mouse harbors PS1M146 V,
APPSwe, and tauP301L mutations and progressively develops
extracellular senile plaques and intracellular neurobrillary
tangles (NFTs) as well as cognitive impairments [244].
Interestingly, even the exogenous antioxidant systems seem
to fail in AD, which are apparently not related to undernourishment because, as demonstrated in 79 patients where
the plasma chain-breaking antioxidants a-carotene,
b-carotene, lycopene, vitamin A, vitamin C, and vitamin
E were measured by HPLC in addition to a total antioxidant capacity assay, a tool for measuring the inhibitory
eect of antioxidants [245]; all of the measured parameters
were below the normal range.

Microglia activation and neuroinflammatory

response
A common factor in AD pathogeny is the overactivation of
microglia with the consequent overexpression of proinammatory cytokines and a signicant increase in ROS [246

248]. ROS, in turn, may come from the innate immune

response promoted by danger signals [249, 250] or from the
damaged mitochondria [251, 252].
Ab peptides may activate microglia through (i) Toll-like
receptors 2 (TLR2), (ii) scavenger receptor (SR), (iii)
receptor for advanced glycation end products (RAGE),
(iv) a cell surface receptor complex, and (v) TNFR1, whose
deletion, as observed in APP23 transgenic mice (APP23/
TNFR1()/))), may inhibit Ab generation and diminishes Ab
plaque formation in the brain [253]. Ab aggregates as
foreign protein particles are recognized by TLRs, and these
become important Ab innate immune receptors, as demonstrated in antisense knockdown of TLR2 or using
functional blocking antibodies against TLR2, which may
suppress Ab-induced expression of proinammatory molecules and integrin markers in microglia [254]. Even TLR4
could also play a role, as demonstrated in mouse models
homozygous for a destructive mutation of TLR4; these
show signicant increases in diuse and brillar Ab
deposits [255]. However, it is not clear whether TLR
signaling pathways involve the clearance of Ab deposits in
the brain or they initiate a neuroinammatory response,
responsible for the synaptic impairment observed in AD
pathology [256]. Important receptors, such as the class B
scavenger receptor CD36 and the LPS-binding molecule
CD14, signal through TLR2. CD36 recognizes a variety of
ischemic by-products acting as ligands, including oxidized
low-density lipoprotein (LDL), long-chain fatty acids,
thrombospondin-1, and, again, Ab. In microglia and in
other tissue macrophages, Ab initiates a CD36-dependent
signaling cascade involving the Src kinase family members,
Lyn and Fyn, as well as the mitogen-activated protein
kinase, p44/42. Ab also causes the blockade of Src kinases
downstream of CD36 and inhibits macrophage inammatory responses to b-amyloid [257].
Another scavenger receptor, the macrophage receptor
with collagenous structure (MARCO) along with the chemotactic G-protein-coupled receptor formyl-peptide-receptor-like-1 (FPRL1) has been documented to be essential in
the amyloid b-induced signal transduction in glial cells [258].
Neurons, microglia, and endothelial cells, which surround
the senile plaques in the AD brain, express higher levels of
RAGE, which may trigger oxidative stress and NF-jB
activation [259]. The interaction of Ab with RAGE may be a
direct interaction [216], or it may involve damaged molecular
patterns, such as the S100B protein. In primary cortical
neurons, the transcription factor Sp1 mediates IL-1b induction by S100B without evidence of a role for NF-jB, whereas
in microglia, S100B stimulates NF-jB or AP-1 transcriptional activity and upregulates Cox-2, IL-1b, IL-6, and TNFa expression through RAGE engagement [260, 261]. Finally,
a cell surface receptor complex for brillar Ab, linked to the
small GTPase Rac1 and critical in signaling to PHOX, has
been described. This molecular complex mediates microglial
activation through the stimulation of intracellular tyrosine
kinasebased signaling cascades, and it is integrated by the
B-class scavenger receptor CD36, the integrin-associated
protein/CD47, and the a6b1-integrin [262].
NF-jB may be activated from a variety of pathways,
from the canonical pathway where the proinammatory
TNF-a, IL-1, and LPS exert their action in addition to
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Rosales-Corral et al.
DAMPS, to the noncanonical pathway where CD40 and
lymphotoxin receptors activate a p52/relB complex. Moreover, there are other atypical pathways, where genotoxic
stress, hypoxia, UV light, H2O2, or the epidermal growth
factor receptor 2, among others, may intervene (reviewed in
[263]). The link between NF-jB and neurodegenerative
disorders, particularly AD, is an old one [264, 265].
In rat primary cultures of microglial cells and human
neutrophils and monocytes, Ab activates PHOX, and this
eect may be potentiated by the proinammatory stimulus,
such as interferon-gamma or TNF-a, but blocked by
tyrosine kinase inhibitors [266]. Mediated by PHOX,
oligomeric Ab may induce ROS production, possibly
through N-methyl-D-aspartate receptors (NMDAR), and
these PHOX-related ROS, in turn, release the prostanoid
precursor arachidonic acid through the activation of ERKs,
which phosphorylate cytosolic phospholipase A2a [219].
The rate-limiting enzyme, COX-2, can be induced by
multiple cellular factors such as growth factors or the
proinammatory cytokines IL-1b and TNF-a in neurons,
astrocytes, and microglia. COX-2 in turn regulates PGE2
signaling in neurons [267] and can activate APP transcription in astrocytes [156], as well as glutamate release from
astrocytes, which is responsible for excitotoxic damage in
AD [193, 268, 269]. PGE2 and COX-2 feedback each other
and modulate neuroinammation, regulating the production of multiple inammatory molecules.

Melatonins role in neuroinflammation and

oxidative stress
Importantly, melatonin has a key role in Ab-induced
assembly of PHOX and the subsequent production of
ROS, as demonstrated in cultures of microglia incubated in
the presence of brillar Ab. According to Zhou et al. [270],
melatonin may impair the assembly of PHOX by inhibiting
the translocation of p47phox and p67phox subunits of
PHOX from the cytosol to the plasma membrane. This
becomes feasible owing to blockade of the phosphorylation
of p47phox, a PI3K-dependent phenomenon, and consequently impairing the binding of p47phox to gp91phox.
This mechanism is related to melatonins capacity to inhibit
Akt (protein kinase B) activity in microglia, which is the
Ser/Thr kinase downstream of PI3K in these cells [270]. It is
worth mentioning that the activation of the PI3K/Akt
pathway may be mediated by H2O2, acting as an intracellular messenger [271]; melatonin is known to directly
scavenge H2O2 [234, 239] (Fig. 7).
Melatonin directly detoxies H2O2 and produces the
biogenic amine AFMK and a potent free radical scavenger,
which in turn may suer deformylation, giving rise
AMK.This latter antioxidant and free radical scavenger is
particularly relevant in mitochondria [78, 157, 239] (Fig. 7).
Melatonin and/or its metabolites function as antioxidants
[91, 272], free radical scavengers, and antiapoptosis agents
and prevent abnormal nitric oxide (NO) elevation [273] in
the cerebral cortex.
Between microglia and astrocytes, a uid communication
exists. Several astrocyte factors released including transforming growth factor b (TGF-b), macrophage colonystimulating factor, granulocyte/macrophage colony-stimu178

lating factor, IL-10, IL-b, and ApoE modulate microglia

activity [274276]. Glial Ca2+ waves can trigger responses
in microglial cells, and the calcium waves arise, in vitro, in
response to Ab administration [277]. Extracellular ATP, in
its role as a DAMP and as part of the innate immune
receptor surveillance behind the Ab-induced inammasome
activation [278], may also elicit Ca2+ waves and activate a
microglial inammatory response [279]. As will be explained below, melatonin also has a role in this process.
Even though the underlying mechanisms and their scopes
in neuroinammation remain to be unveiled, it has been
suggested that melatonin could have modulatory eects on
ATP-dependent gliotransmission or glial calcium waves
derived from dierent brain regions and species, regulating
astroglial function [280]. Studied in the context of rhythmic
circadian outputs to pervasive neurobehavioral states, a
functional shift in the mode of intercellular communication
between junctional coupling and calcium waves in glial cells
was found to be induced by melatonin [281]. However, it is
well known that melatonin modulates intracellular free
Ca2+, and by this means, melatonin may protect cells from
calcium-dependent pathways of death, such as calpain and
caspase-3 in cells undergoing excitotoxicity and oxidative
stress, as demonstrated in vitro in rat C6 astroglial cells
[282]. By controlling Ca2+ inux, melatonin attenuates
glutamate-mediated excitotoxicity, which is responsible for
NMDAR-mediated damage of neurons. This in turn is one
of the postulated Ab-mechanisms of damage, as mentioned
above [219]. In in vitro experiments with a hippocampal cell
line challenged with H2O2, Ab, or glutamate, cell death was
prevented by the melatonin derivative, AFMK, which is
formed by the interaction of melatonin with H2O2 or O_2
[76] (Fig. 7). Additionally, melatonin may inhibit not only
glutamate-induced ion currents but also ion currents from
the other ionotropic glutamate receptors, kainate, and
AMPA [283]. Also, it is possible that melatonin antagonizes
glutamate release, as observed in cortical synaptosomes in
old mice and in neurotoxicity induced by KCl [284].
We reported in vivo that melatonin signicantly reduced
the proinammatory response, decreasing by nearly 50%
the Ab-induced levels of proinammatory cytokines IL1-b,
IL6, and TNF-a [285]. We speculated that melatonin
aected NF-jB DNA binding activity based on a previous
report by Natarajan et al. [286]and Chuang et al. [287],
who found that NF-jB DNA binding activity was inhibited
by melatonin and was lower at night when endogenous
melatonin levels are high. Furthermore, 60 min after an
intraperitoneal injection of melatonin, a reduction in NFjB DNA binding activity was replicated. More recently, it
has been demonstrated in Ab-treated brain slices that
melatonin reduces NF-jB-induced IL-6 in a concentrationdependent manner [288]. By administering melatonin, it is
also possible to reduce Ab-induced impairment in learning
and memory in rats along with a signicant decrease in
positive glial cells expressing NF-jB-induced IL-1b in
addition to C1q in hippocampus [289], both of which are
involved in glial activation (Fig. 7). The critical complement component C1q, in turn, may induce the translocation
of NF-jB p50p50 homodimers, at least as observed in
human monocytes [290], and it is always related to AD
pathology usually linked to brillar b-amyloid [291].

Alzheimers disease and melatonin

The pleiotropic transcription factor NF-jB, composed of
homo- and heterodimers of ve members of the Rel family
including NF-jB1 (p50), NF-jB2 (p52), RelA (p65), RelB,
and c-Rel (Rel) plays a key role in inammatory processes
but also it is a protagonist in plasticity and neuronal
development (reviewed in [292]). Thus, it is complicated to
point out that NF-jB inhibition may be a therapeutic target
in AD. Nonetheless, by using an immunological assay, it is
possible to demonstrate how melatonin prevents the Abinduced expression of NF-jB [147]; more specically,
according to Deng et al. [293], melatonin inhibits p52
NF-jB binding as demonstrated by examining the expression of LPS-induced iNOS and COX-2. The latter action
involves a promiscuous histone acetyltransferase (HAT),
within the nuclear cofactor p300, which is essential for
COX-2 transcriptional activation by proinammatory
mediators. By inhibiting p300 HAT activity, melatonin
may suppress p52 acetylation, binding, and transactivation
[293]. In this manner, it is possible to block the rate-limiting
enzyme COX-2 (Fig. 7). This enzyme is induced by multiple
cellular factors, such as growth factors or the proinammatory cytokines IL-1b and TNF-a in neurons, astrocytes,
and microglia. COX-2 in turn regulates PGE2 signaling in
neurons [267] and can activate APP transcription in
astrocytes [156], as well as glutamate release from astrocytes, which is responsible for excitotoxic damage in AD
[268, 269, 293]. PGE2 and COX-2 feedback on each other
and modulate neuroinammation, regulating the production of multiple inammatory molecules.
Experiments using transformed lymphatic-derived endothelial cell line demonstrated the ability of melatonin to
prevent TNF-a induced phosphorylation of NF-jB p65,
although the mechanism is unclear [294]. The administration of melatonin 1 hr after closed head injury also may
inhibit the activation of NF-jB during the late phase
(8 days), an eect attributed to its prolonged antioxidant
eect at the site of injury. However, melatonin did not alter
early phase (24 hr after closed head injury), which implies a
selective mechanism of neuroprotection [295]. One could
expect that such an interference with NF-jB would also
aect the role of this transcription factor in plasticity and
neurogenesis. Thus, even though not linked to these NFjB-dependent mechanisms, there are reports indicating a
signicant depression as well as instability of synaptic
transmission in the central nervous system (CNS),
although melatonin-dependent uctuations in synaptic
potentials were apparent only when the involved circuit
was tetanized [296]. Such depressive eects of melatonin in
synaptic transmission would be expected to inuence
epileptic seizure activity [297]. Nonetheless, other results
indicate that, instead of depressing synaptic transmission,
melatonin modulates neuronal excitability in the hippocampus, and this modulatory activity depends on its
receptors [298, 299]. In fact, melatonin may modulate
specic forms of plasticity in hippocampal pyramidal
neurons, as demonstrated by electrophysiological methods
[300] where neurons exposed to melatonin were found to
change their excitability in response to repetitive stimulation, which reveals melatonin as an activity-dependent
modulator of subsequent synaptic plasticity (metaplasticity; Fig. 4).

It seems that melatonin may thus regulate neuroinammation through free radical control and modulation of
important proinammatory transcription factors and their
signaling pathways while reducing glutamate excitotoxicity,
whether it be by inhibiting glutamate-induced ion currents
or by controlling the glutamate delivery. On the other hand,
even though functional cytoplasmic membrane melatonin
receptors have been described in astrocytes derived from
chick brain [301], which could suggest a role for melatonin
as a metabolism regulator in astrocytes, these receptors
have not been corroborated in human glia.
The nuclear hormone retinoid z receptor/retinoid orphan
receptor (RZR/ROR), from the retinoid-related orphan
receptors family, are likely associated with melatonin
signaling and have been identied in the promoter region
of 5-lipoxygenase (5-LOX), a key protagonist in neuroinammation. By repressing the expression of 5-LOX mRNA
in human B lymphocytes, melatonin may reduce the
proinammatory response via nuclear receptor RZR/
RORa [302]. Furthermore, the transcriptional activation
of RZR/RORa by melatonin is possible even in the
nanomolar range [303, 304]. There are no reports conrming this eect of melatonin in the CNS, but 5-LOX is widely
expressed in the brain [305] where it has neuromodulatory
and neuroendocrine functions and plays an important role
in aging and AD, as we will review later. It is worth
mentioning that, in addition to AA-derived leukotrienes,
5-LOX also modulates the c-secretase activity in membranes, favoring Ab formation [306].
Although there is an isolated report indicating that
melatonin is not an important modulator of macrophage
and microglia function [307], melatonins role controlling
the
primarily
microglia-guided
neuroinammatory
response is demonstrated in multiple reports. This is a
consequence of its regulation of the NF-jB overexpression
[308], the amount of LPS-induced proinammatory cytokines [192], or prevention of GSK-3b activation and
neuroinammation in response to Ab, as observed in
astrocytes and microglial cells [166]. Meanwhile, a cumulative dose of 10 mg/kg melatonin may attenuate kainic
acid-induced neuronal death, lipid peroxidation, and microglial activation, reducing the number of DNA breaks in
vivo, as demonstrated in adult male SpragueDawley rats
[309].
The antioxidant and immunomodulatory eects have
inserted melatonin into the two-hit hypothesis [310], which
states that although either oxidative stress or abnormalities
in mitotic signaling can, independently, serve as initiators in
AD, both processes are necessary to propagate the pathological features of the disease.

The mitochondrial cascade hypothesis

According to Swerdlow and Khan [311], the mitochondrial
cascade hypothesis asserts that inheritance determines
mitochondrial baseline function and durability, and mitochondrial durability inuences how mitochondria change
with age. Thus, according to this hypothesis, once a
threshold of mitochondrial changes is reached, AD histopathology and symptoms ensue. Even though it was
formulated in 2004 as a formal hypothesis, some strong
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evidence linking AD to mitochondrial damage in brain
cells had been reported many years earlier. For example,
in 1980, by investigating the mechanism for the production
of acetyl-CoA used in acetylcholine synthesis, a small, but
signicant, reduction in the activity of the pyruvate
dehydrogenase (besides ATP-citrate lyase and acetoacetyl-CoA thiolase) was found in postmortem brain tissue
from cases of AD [312]. In 1985, the activity of the
pyruvate dehydrogenase complex was reported to be
reduced to about 30% of control values in histologically
unaected occipital cortex as well as in histologically
aected frontal cortex of the brains of patients with AD
[313]. Likewise, AD as a primary defect in cytochrome
oxidase was proposed years later [314]. However, it
currently is debatable whether Ab is a downstream
product of the mitochondrial functional decline or whether
Ab-induced mitochondrial damage is an extension of the
amyloid cascade hypothesis. The amyloid cascade, proposed 20 yr ago, suggested that faulty metabolism of APP
was the initiating event in AD pathogenesis, leading
subsequently to the aggregation of Ab, specically Ab1
42 [315, 316]. However, long before the appearance of
extracellular Ab deposits, they are detectable within
mitochondria [317].
Beyond hypotheses, some other important features have
been found since those early years. It has been demonstrated that Ab142 uncouple the mitochondrial respiratory
chain, and this event plays a key role in pathology of AD
[311]. Structurally, Ab induces swelling of isolated mitochondria [318, 319] and, functionally, decreases ATP
synthesis and the activity of various mitochondrial enzymes, as demonstrated in vivo [320] and in vitro in
cultured neuronal cells or in Ab-exposed astrocytes [319
321]. Later, dierent neurotoxic mechanisms for Ab were
proposed, including disruption of mitochondrial function
via binding of the Ab-binding alcohol dehydrogenase
(ABAD) protein [322]or the formation of ion channels
allowing calcium uptake, which induces neuritic abnormality in a dose- and time-dependent manner [323], or the
opening of the mitochondrial permeability transition pore
coupled to inhibition of respiratory complexes [324, 325].
We have found (Rosales-Corral et al., unpublished data)
that following the intracerebral injection of brillar Ab, the
peptide is revealed both intracellularly and intramitochondrially, deep in the cristae, coinciding with other reports
which demonstrate that Ab progressively accumulates in
mitochondria where it is associated with diminished enzymatic activity of the respiratory chain complexes III and IV
[317]. Presence of Ab in mitochondria is related to a
reduction in the rate of oxygen consumption by the electron
transport chain [317]. The enzymes in charge of importing
Ab to mitochondria have been identied as a complex of
translocases, i.e., translocases of the outer membrane
(TOM) and the translocase of the inner membrane (TIM)
[326] (Fig. 8).
In addition to direct eects caused by Ab in mitochondria, there are severe changes attributed to the Ab-induced
oxidative stress. A disturbance of mitochondrial dynamics,
a term that includes ssion, fusion, movement, and
mitochondrial architecture, seems to be implicated in
AD pathogeny. It has been demonstrated in human brains
180

of patients with AD where mitochondrial distribution

tends to be predominantly perinuclear and ssion or
fragmentation prevails over fusion, a phenomenon related
to a low metabolic capability [327, 328]. These events
involve large dynamin-related GTPases, such as the
dynamin-related protein (Drp1). Localized to mitochondria, Drp1 is a key factor in mitochondrial division and
particularly sensitive to redox regulation [328]. It has been
reported that NO overproduced in response to Ab protein
could be responsible for the impairment of Drp1 via
S-nitrosylation [329], and this eventuality may lead to an
imbalance of ssion/fusion in mitochondria, which in turn
is correlated with neuronal damage and synaptic loss
[330].
Another important feature related to AD pathogeny is
mtDNA damage. Perhaps because it is not protected by
histones, mtDNA with its 37 genes is more susceptible to
oxidative stress-induced deletions and point mutations
than nuclear DNA. Even though the consequences of
these alterations remain to be claried [331], mtDNA
damage is usually linked to dysfunction (decrement of
mitochondrial electron transport chain eciency) and
apoptosis [332, 333].
Also related to Ab-induced oxidative stress, mitochondrial proteins and lipids become disturbed leading to
dysfunction. We have found signicant alterations in
cholesterol and fatty acids content in mitochondrial membranes following the injection of Ab (Rosales-Corral et al.,
unpublished data), associated with functional impairment;
as a consequence of increased membrane permeability and
changes in lipid polarity owing to oxidative injury,
cytochrome c is released from the intermembrane space of
mitochondria [334], behaving as an important intermediate
in apoptosis and associated with impaired mitochondrial
respiration, as observed in brain, platelets, and broblasts
of patients with AD [335].
An important feature related to the direct interaction
between Ab and cyclophilin D (CypD) has been found
[336]. Ca2+-associated CypD is part of the mitochondrial
permeability transition pore (MtPTP) and translocates
from the matrix to the inner membrane where it appears
linked to oxidative stress, and by facilitating the opening of
mPTP, CypD causes mitochondrial swelling with cellular
and synaptic perturbations [337, 338]. The importance of
the association of Ab/CypD is underlined by the fact that a
deciency in CypD may attenuate Ab-induced mitochondrial oxidative stress, an eect accompanied by improved
synaptic function and an improved cognitive performance,
as observed in APP transgenic/CypD double-mutant mice
[336] (Fig. 8).
As a result of Ab entrance and mitochondrial damage,
energy demands of cells become impaired. We have found
functional disorders of F0F1-ATPase in submitochondrial
particles obtained from platelets of patients with Alzheimers-type dementia [339], but the impairment of ionmotive ATPases in response to Ab is reproducible in
hippocampal neurons in culture [340]. Nonetheless, another
report on F0F1-ATPase, searching in isolated mitochondria from platelets and postmortem motor cortex and
hippocampus from patients with AD, did not nd abnormalities in F0F1-ATPase functioning [341].

Alzheimers disease and melatonin

Fig. 8. Both Ab and abnormal phosphorylated tau play key roles in mitochondrial dysfunction long before amyloid plaques appear.
Hyperphosphorylated tau may cause ETC dysfunction by impairing complex I activity, although its major capacity for damaging may come
from its ability to interact with ANT from MtPTP, which leads to swelling, mitochondrial dysfunction, and cell death, ultimately. Amyloidb, whose mitochondrial receptors (ABAD and Hsp) have been identied, causes ETC dysfunction by interrupting the activity of complex III
and complex IV, and possibly it may disrupt ion-motive ATPase. Moreover, Ab impairs energy metabolism by inhibiting directly the activity
of the a-ketoglutarate enzyme during the tricarboxylic acid cycle and the pyruvate dehydrogenase before the cycle. Ab also disrupts Ca2+
homeostasis, which overloads mitochondrial matrix and may lead to complex II deciency, membrane potential loss, ATP reduction, and
ROS overproduction in addition to MtPTP disturbance. Ab-induced oxidative stress has been related to membrane dysfunction, oxidation
of ETC components, free radical leak, and MtDNA damage because MtDNA is particularly vulnerable to these events. The way CytC
escapes from mitochondria is not completely clear, but once released, it initiates a chain of events leading to apoptosis. Melatonin
(represented as red crosses) tends to accumulate inside mitochondria, where (1) it may reduce oxidative stress and its deleterious consequences on MtDNA, proteins, and membrane lipids, such as cardiolipin; (2) it strongly inhibits MtPTP currents and prevents cytochrome c
release in a dose-dependent manner; (3) it may recycle electron carriers, such as NADH; (4) it may prevent apoptosis by impairing Cytc
release from mitochondria; (5) Ca2+ regulation by melatonin may protect mitochondrial functioning. ROS/RNS, reactive oxygen/nitrogen
species; Ub, ubiquitin; ABAD, amyloid-b binding alcohol dehydrogenase; Hsp, heat-shock protein; Cytc, cytochrome c; ETC, electron
transport chain; MtPTP, mitochondrial permeability transition pore; MtDNA, mitochondrial DNA; APAF-1, apoptosis-activating factor 1.

Melatonins role in mitochondrial

hypothesis
Melatonins role in this context is mostly related to its
ability to scavenge free radicals in addition to its indirect
antioxidant properties because it enhances endogenous
antioxidant systems in mitochondria [342348]. It does this
basically by maintaining and regenerating the GSH content, which is an important antioxidant mechanism in
mitochondria [346]. Similarly, melatonin reduces peroxidation of lipids in mitochondrial membranes and free radical
leakage from this organelle. Thus, it is possible to reproduce in vitro mtDNA damage by adding Ab142 to neurons
in culture, but the addition of melatonin prevents signicantly mtDNA damage [14, 347]. Added to drinking water
and chronically administered, melatonin prevents mitochondrial impairment, maintaining or even increasing ATP
production in senescent-prone mice suering age-dependent
mitochondrial dysfunction accompanied by an important
oxidative/nitrosative stress [348]. It is worth noting that,
additionally, melatonin seems to accumulate in the mitochondria, in such a manner that mitochondrial melatonin

levels could be even 100 times higher than melatonin levels

in plasma [346]; this claim, however, requires conrmation.
Indole propionamide, similar to melatonin but with a
longer half-life has been proven to protect against mitochondrial toxins capable of collapsing the mitochondrial
proton potential, causing severe mitochondrial dysfunction
and ATP deprivation. Under those circumstances, this
recently discovered endogenous indole may act as a
recyclable electron and proton carrier, restoring the proton
gradient and mitochondrial ATP synthesis [349].
In reference to MtPTP, the antiapoptotic eects of
melatonin have been explained by its ability to inhibit the
opening of the protein channels responsible for calcium and
cytochrome c (cyt c) release from mitochondria. Also, it
may function by reducing the loss of the mitochondrial
membrane potential in the presence of glucose deprivationrelated events [350] (Fig. 8).
Cardiolipin is an important component (20%) of the
inner mitochondria membrane. Being particularly susceptible to oxidative stress, cardiolipin becomes implicated in
cyt c release during apoptotic events [351], in part because it
sensitizes mitochondria to Ca2+ mPTP [352]. One of the
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probable mechanisms of mitochondrial protection by
melatonin relates to the prevention of cardiolipin oxidation,
avoiding MtPTP opening and restoring Ca2+ balance (as
reviewed in [353]). However, it is also possible that
melatonin directly inhibits MtPTP at single-channel and
cellular levels, as demonstrated in patch-clamp recordings
on the inner mitochondrial membrane [350].
Three other important proapoptotic factors related to
mitochondrial functioning and signaling have been demonstrated to be modulated by melatonin in brain. The
executory caspase-3, which is known to be directly linked to
cyt c release and widely linked to cell death in AD [99, 320,
354], can be downregulated by melatonin [92]. On the
contrary, melatonin may enhance bcl-2 expression as
demonstrated in AD transgenic mice [92] and in ischemic
brain [355]. Bcl-2 is recognized as an antiapoptotic protective factor, and its relation to Ab is also widely known,
because Ab may deplete bcl-2 as demonstrated in human
primary neuron cultures [356], in microglia [357], or in
human neurons from patients with AD [358]. Furthermore,
the proapoptotic bcl-2associated X protein (Bax), which
moves from the cytosol to the mitochondria, binds to bcl-2,
and promotes cyt c release, is increased in the presence of
Ab in human neurons [356]. However, under a variety of
experimental conditions, melatonin has demonstrated its
utility in diminishing bax [174, 359361]. Thus, melatonin
modulates mitochondrial pathways to apoptosis.
Mitochondrial damage is linked not only to energy
dysmetabolism and leakage of free radicals, which in turn
feeds back to induce oxidative stress, but also to increased
leakage of Ca2+ currents, besides the above-mentioned
apoptosis-inducing factors.

Calcium hypothesis
Other hypotheses have been proposed, complementing the
amyloid cascade theory. For example, it has been proposed
that a calcium-signaling decit causes accumulation of APP
because APP a-processing is a Ca2+-dependent process,
and this phenomenon provides excessive substrate for
b- and c-secretases, the enzymes responsible for APP
processing and Ab overproduction (Fig. 1) [362]. That Ab
increases calcium uptake has been demonstrated in PC12
cells [363], in human cortical neurons linked to glutamate
excitotoxicity [364], in AD brain frontal cortex, and in
plasma membrane vesicles from both rat and human brain
[365]. This occurs via stimulation of L voltage-sensitive
calcium channels, as demonstrated in cultured neurons
[366], but Ab also may increase calcium uptake via
potassium channels, the NMDA receptor, the nicotinic
receptor, or even by its own calcium-conducting pores
(reviewed in [367]). Conversely, calcium accelerates Ab
aggregation, even at physiological concentrations [368], and
it is exacerbated by synthetic calcium ionophores [369]. At
the same time, Ab-induced calcium waves feed the neuroinammatory response, and this increases Ab aggregation
and calcium waves, as mentioned previously [277279].
During the events leading to oxidative stress and neuroinammation in AD pathogeny, the glutamate-override of
the glutamate/cystine-antiporter system, which controls the
levels of glutamate by exchanging cystine in cells for the
182

neurotransmitter glutamate, may lead to an excessive

glutamate activity and consequently excessive inux of
cations, Ca2+ in particular [268, 269]. Glutamate receptors,
especially NMDA, are deeply involved in AD pathology
[370]by controlling Ca2+ inux. Ionic calcium, in turn,
activates a number of enzymes, including phospholipases,
endonucleases, xanthine oxidase, neuronal nitric oxide
synthase, as well as proteases, such as the calcium-dependent cysteine protease, calpains, among others [190, 269,
338, 367, 369]. Thus, the glutamate-induced overestimation
of NMDA receptors becomes neurotoxic; this process is
common to several neurodegenerative diseases, and it is
well known as glutamate excitotoxicity (reviewed in [269]).

Melatonins role in calcium hypothesis

Melatonin may reduce NMDA-induced high [Ca2+]c levels
in addition to its ability to directly inhibit the mitochondrial
permeability transition pores, a mechanism linked particularly to oxidative stress, as mentioned before [350]. Several
other mechanisms have been postulated to explain the
regulation of intracellular Ca2+ by melatonin. As an
example, it is possible that melatonin acting on its MT2
receptor may inhibit adenylyl cyclase, and with this, it
decreases cAMP formation, blocking the cAMP-dependent
protein kinase (PKA), which would activate calcium release
channels [370372]. The reader is reminded that pineal and
cortical melatonin receptors, MT1 and MT2, are signicantly decreased in AD brain [373]. Conversely, it has been
known from many years that calcium inux regulates
melatonin production in the pineal gland [374] (Fig. 9).
Melatonin also may inhibit the mobilization of Ca2+
from ER as well as Ca2+ inux through voltage-sensitive
channels [375]. Importantly, melatonin controls the
NMDA receptor whose activation comprises multiple
regulatory sites controlling Ca2+ inux into the cell. On
the contrary, in the presence of the Ca2+ ionophore A23187, the inhibitory eect on Ca2+ by melatonin is
suppressed [376], returning to a glutamate-derived excitatory state. The mechanism involved in NMDA-R control
may also imply redox modulation [350, 377]. However, it is
also possible that melatonin increases the concentration of
the NMDA receptor subunits 2A and 2B, as demonstrated
in rat hippocampus, in a dose-dependent manner [378].
Another melatonin mechanism of protection related to
calcium inux control is the multifunctional calciummodulated protein (calmodulin, or CaM) [379], which
mediates the calcium requirement for retrograde axonal
transport of AchE [380]. Melatonin interaction with CaM is
so avid that CaM had been considered a receptor for
melatonin [381, 382] (Fig. 4). Even though more recent
NMR and molecular dynamic studies suggest a lower
anity [383], it has been demonstrated that melatonin
decreases, in a specic manner, the activity and autophosphorylation of CaM kinase II, a key protein kinase
involved in neurite maturation [384], and causes neurite
enlargement through an increase in tubulin polymerization
derived from its CaM antagonism [385, 386]. In this
manner, apart from its antioxidant and antiapoptotic
eects as well as its anti-AchE actions related to Ca2+
and CaM modulatory eects, melatonin may preclude

Alzheimers disease and melatonin

Fig. 9. Some of the most relevant issues in the calcium hypothesis are related to the following: (1) its functional association with c-and bsecretase activity; thus, APP amyloidogenic processing seems to be a Ca2+-dependent process; (2) Ab, in turn, facilitates Ca2+ uptake using
a variety of calcium channels; (3) Ca2+ accelerates Ab aggregation, which in turn causes neuroinammation, oxidative stress, and glutamate
release; (4) calcium massive entrance causes excessive accumulation of Ca2+ within ER and mitochondria, one dysfunctional and apoptosisrelated phenomenon; (5) dysregulated intracellular Ca2+ activates a number of enzymes including CaM, which in turn activates CaMdependent kinases responsible for tau phosphorylation; (6) cytosolic PLA2 is also a Ca-dependent enzyme and, when activated, causes
arachidonic acid release and the subsequent activation of the neuroinammatory pathway via COX-2. Reports on melatonin (red crosses)
reveal a role for it: (1) as a free radical scavenger and antioxidant, (2) as an antiamyloidogenic, (3) as an inhibitor of Ca2+ inux, (4) as a
CaM antagonist, and melatonin also may impair Ca2+ leaking from ER, and (5) by regulating calreticulin, it is tempting to speculate that
melatonin may delay ER stress. APP, amyloid precursor protein; ROS/RNS, reactive oxygen and reactive nitrogen species; bs, beta
secretase; cs, gamma secretase; NMDA-R, n-methyl-daspartate receptor; L-Type R, voltage dependent L-type calcium receptor; AC,
adenylyl cyclase; cPLA2, cytoplasmic phospholipase A2; AA, arachidonic acid; ER, endoplasmic reticulum; UPR, unfolded protein response; MIT, mitochondria; CaM, calmodulin.

microlament and microtubule collapse, as demonstrated in

N1E-115 cells [372]. Even more, by activating the Ca2+dependent a isoform of PKC [387], melatonin may restore
neurite formation, microtubule enlargement, and microlament organization in microspikes and growth cones in
cells damaged with H2O2. On the contrary, the PKC
inhibitor, bisindolylmaleimide, blocks neurite formation
and microlament reorganization elicited by melatonin.
Thus, by regulating Ca2+ and CaM, melatonin possesses
modulatory actions on cytoskeletal protein phosphorylation, suggesting that it may re-establish neurite formation
and the basal levels of phosphorylated tau, at least in N1E115 cells treated with okadaic acid [388, 389].
There is another Ca2+-related melatonin receptor, which
may be relevant in AD, i.e., calreticulin (CRT) [390]. This
ER resident protein is known to have a role in the folding
and assembly of oligomeric membrane proteins. In fact,
CRT may function as a molecular chaperone for the Ab
precursor protein, as it has been demonstrated in HEK 293
cells transfected with APP [391]. Calreticulin may initiate

ER stress, so it is tempting to speculate that ER stressinduced CRT augments the folding capacity of the ER. By
regulating calcium inux and release within the cytoplasm,
melatonin regulates not only cellular homeostasis but
apoptosis as well (Fig. 9).
It is obvious that in addition to the inhibition of ER and
mitochondrial-related mechanisms of apoptosis, melatonin
may also prevent spontaneous neuronal apoptosis by acting
on downstream signal targets of the protein kinase B or
Akt: the forkhead box protein O1 (FOXO-1) and the GSK3b [392]. Akt is linked to the PI3-K/Akt survival pathway
and is required for the expression of long-term potentiation
in learning and memory. It is also linked to the insulin
receptor substrate (IRS) for the purpose of regulating
glucose uptake through a series of phosphorylation events.
Moreover, PI3K is phosphorylated upon NMDA receptordependent CamKII activity [393], which is also a melatonin
target, as mentioned above [386388]. According to Tajes
et al. [392], melatonin increases the activation of prosurvival PI3K/Akt, whereas it inhibits GSK-3b and causes an
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increase in FOXO-1 phosphorylation. This is a proapoptotic transcription factor involved in insulin activity and in
the cellular response to oxidative stress. Finally, GSK-3b,
primarily linked to the inactivation of the glycogen
synthase, has been also associated with AD and frontotemporal dementia [394] where it is related to microtubule
stability because it phosphorylates the microtubule-associated protein tau [395] whose hyperphosphorylation is an
early event preceding the appearance of neurobrillary
tangles (NFT) in AD (Fig. 10).

Fig. 10. Ab and other associated events, such as high cholesterol

levels, have insulin resistance in common. Insulin resistance interrupts the neuroprotector PKB/Akt pathway, leading to activation
of GSK3 and diminishing IDE levels. Once GSK3 becomes active,
it phosphorylates tau while increasing Ab production, because
GSK3 is required for the amyloidogenic processing of APP. IDE,
normally stimulated by Akt, reduces its function under insulin
resistance conditions. In this manner, insulin degradation is avoided. However, because amyloid is also a target for IDE, Ab degradation decreases in parallel with the former event, and the
neurotoxic peptide tends to accumulate as a consequence and
competes for insulin binding to the insulin receptor. Ab may even
inhibit IDEs activation by interfering with the PI3K/PKB/Akt
pathway. There are reports indicating that melatonin (red crosses)
(1) may increase IGF-1 levels, (2) may activate the insulin receptor
b-subunit tyrosine kinase, which then phosphorylates and activates
IRS, (3) may activate directly the PI3K/PKB/Akt pathway through
its MT receptors, and (4) may act on CaMKII melatonin inhibits
tau phosphorylation, but if CaMKII were responsible for PI3K
activation (above left), then it would inhibit the PI3K/PKB/Akt
pathway. MT, melatonin receptors; IGF-1, insulin-like growth
factor; IR, insulin receptor; PI3K, phosphoinositide 3 kinase; IRS,
insulin receptor substrate; PIP, phosphatidylinositol bis- and triphosphate; PDK-1, Phosphoinositide-dependent kinase; CREB,
cAMP response element binding; FOXO-1, Forkhead box protein
O1; IDE, insulin-degrading enzyme; GSK3, Glycogen synthase
kinase; ADDL, Ab-Derived Diusible Ligands.

184

Insulin resistance hypothesis

As can be seen, a number of glucose metabolism related
factors begin to appear. GSK-3b is closely controlled by
Akt and insulin signal transduction [162], while GSK-3a
increases Ab production [139]. Insulin-activated PI3K-Akt
signaling pathway may be interfered with by Ab [396], and
it is well known that an impaired insulin signal transduction
is involved in AD pathogeny [397]. On the other hand, the
redox-sensitive insulin-degrading enzyme, IDE [398], the
most important degradative system for insulin and insulinlike growth factor 1 (IGF-1), is also a major Ab-degrading
enzyme [399]. All of this leads us to another hypothesis,
which is provocative because it links AD to diabetes,
mitochondrial dysfunction, obesity, and even the cholinergic hypothesis (reviewed in [400]) (Fig. 10).
Also linked to Ab aggregates and oxidative stress, this
insulin resistance hypothesis involves IGF-1 and maintains
that a reduced input of this hormone, by causing insulin
resistance in the brain, may be the primary pathogenic
event in late-onset AD [401, 402]. In fact, many years before
the protective eect of IGF-1 in hippocampal neurons in
vitro subjected to Ab toxicity was described [403], epidemiological studies revealed a signicant association between diabetes mellitus and AD [165, 404, 405]. Later, it
was demonstrated that insulin deciency and diabetes
mellitus exacerbate cerebral amyloidosis and behavioral
decits in transgenic mice [406].
Insulin-like growth factor 1 is a natural molecule similar
to insulin, which controls insulin action and is responsible
for promoting growth eects, such as increased nitrogen
retention and cell proliferation. Beyond glucose homeostasis, insulin is involved in cellular transport of Ab, and a lack
of an adequate insulin input has been related to intracellular Ab accumulation [135]. In fact, by feeding Tg2576
mice with an insulin resistance-inducing diet, it is possible
to promote Ab aggregates, to increase c-secretase activities,
and to decrease IDE activity [406]. Ab peptides, particularly
ADDLs, compete for insulin binding to the insulin receptor, making the cell insulin resistant [407], very similar to
IGF-1 receptor [408], and causing IGF-1/insulin dysfunction; this in turn will aect amyloid tracking via the
inappropriate MAPk and PI3K/Akt activation [401]. The
PI3K/Akt pathway also allows for IGF-1 to inhibit GSK3b [409], a kinase involved in the phosphorylation of tau, as
mentioned before, which is another hallmark of AD
pathology.

Melatonins role in the insulin resistance

hypothesis
Male Syrian hamsters receiving melatonin for 10 wk show a
signicant increase in serum levels of IGF-1 [410], while the
protective eect of melatonin on hepatocytes of CCl4exposed rats [411]has been attributed to increased IGF-1
levels [412]. Evaluated in the context of hypoxia-induced
periventricular white matter injury, melatonin reduces brain
damage by enhancing IGF-1 activity, while it diminishes
glutamate release and the proinammatory response
induced by hypoxia [413]. On the other hand, 6 months
after the administration on daily basis of 2 mg of melatonin

Alzheimers disease and melatonin

in elderly women, IGF-I was found to be slightly but
signicantly increased [414].
An explanation as to how melatonin raises IGF-1 levels
is related to melatonin-induced sleep improvement [415].
Sleep disturbances, as observed in obesity or in sleep apnea
syndrome, cause alterations in the growth hormone/IGF-1
system [416]. Sleep restriction, in fact, is related to increased
insulin resistance, as demonstrated both in obese subjects
and in those with AD.
By acting on its receptors, which are present also in the
hippocampus [298, 417], melatonin may induce a rapid
tyrosine phosphorylation and activation of the insulin
receptor b-subunit tyrosine kinase (IR) and downstream
Akt serine phosphorylation [418]. Thus, by using the PI3KAkt signaling pathway, melatonin seems to activate Akt
(although other receptors acting on the same pathway
could also be involved [161]). The activation of Akt may
have at least four consequences: (i) antiapoptotic activity,
especially by reducing p53 transcriptional activity, which is
particularly true in the hippocampus [419], in addition to
the phosphorylative inactivation of proapoptotic factors
such as FOXO-1 [392] and the Bcl-2-associated death
promoter (BAD) [420]; (ii) inhibition of tau hyperphosphorylation and the consequent paired helical lament
formation by inhibiting the tau kinase GSK-3b [392, 409];
(iii) activation in astrocytes of neurotrophic factors such as
cAMP response element binding (CREB) and the glial cellderived neurotrophic factor (GDNF), while the neuroinammatory control and neuronal plasticity are approached
through the astrocytic and neuronal overexpression of
NF-jB; and (iv) the reactivation of IGF-1 could reduce
insulin resistance [397, 421], ameliorate glucose transport
[422], and additionally reduce Ab accumulation from the
cerebral parenchyma [401, 408, 409, 423] (Fig. 10).
Here, it is necessary to look at melatonins role in Akt
signaling. In isolated microglial cells exposed to Ab,
melatonin has shown inhibitory, dose-dependent eects
on the activity of Akt. This impairs the NADPH oxidase
assembly [270] as we have seen before at the purpose of AD
neuroinammatory response. No apparent phospho-GSK3 was detected in those experiments. On the contrary, in
isolated astrocytes, melatonin may induce Akt, and by this
means, it may inhibit GSK-3b [161]. These apparently
contradictory eects may be related to MT1/MT2 dimerization as a mechanism determining the receptor-mediated
biological eects of melatonin [424]. As an example, the
ERK activity is increased by melatonin in mouse neuroblastoma cells that express only MT1 receptors [425],
whereas in human umbilical vein endothelial cells expressing both MT1 and MT2 receptors, ERK is inhibited by
melatonin [426]. However, dierences related to types of
melatonin receptors among astrocytes, microglia, and
neurons have not been established yet, except in injured
white matter of neonatal rats where MT1 and MT2 seem to
be strongly expressed in both astrocytes and microglial cells
and to a lesser extent in neurons and immature oligodendrocyte [427]. In the AD brain, an increased MT1 immunoreactivity in pyramidal hippocampal neurons has been
documented [417], but in this case, dierences between
astrocytes, microglia, and neurons in reference to their
melatonin receptors were not established (Fig. 4). Astro-

cytes express MT1 and MT2 receptors, and both seem to be

necessary to activate the Akt/PI3k signaling pathway [161].
In microglial cells, what or how many melatonin receptors
would be necessary to activate this same pathway, or even if
they are necessary, remains to be claried. By resolving that
question, we might explain some dierences between
neurons, microglia, and astrocytes in response to melatonin. This is relevant in relation to insulin because melatonin
may inuence insulin secretion [428, 429].
Experimental evidence demonstrates that melatonin
improves glucose tolerance and increases insulin receptors
in muscle and the expression of GLUT-4, a glucose
transporter, in addition to glucose clearance from the
blood [430, 431]. A nal explanation describes these
phenomena as protective actions by melatonin to prevent
hypoglycemia during winter dormancy in animals [432]. In
the AD brain, where glucose uptake and metabolism are
impaired even before the appearance of neuronal degeneration [433], melatonin eects might contribute to delay the
progression of the disease, as has been experimentally
demonstrated in Ab-injected mice [147] as well as in highfat-diet-fed insulin-resistant mice [434] or in vitro by using
in C2C12 murine skeletal muscle cells where it was also
shown that the glucose transport amelioration by melatonin may occur via insulin receptor substrate-1/PI3-kinase
pathway [435].
Feeding rabbits a cholesterol-enriched diet also increases
Ab levels in the hippocampus. This is an intriguing
phenomenon, because cholesterol metabolism in the brain
has been widely known to be independent of cholesterol
metabolism in the body. Even more so, cholesterol in the
blood does not pass the blood brain barrier [436]. How
hypercholesterolemia increases Ab levels in the brain may
be explained by the oxidized cholesterol metabolite 27hydroxycholesterol, which, acting on IGF-1 signaling,
activates Akt. This survival promoter may decrease IDE,
while it increases GSK-3 (a and b), and both phenomena
appear associated with elevated Ab levels, as observed in
organotypic hippocampal slices [423] (Fig. 10).

The lipid connection

The rst question is how cholesterol in the blood increases
cholesterol in brain and how cholesterol in membranes
inuences Ab overproduction. Answers to these questions
would help to explain why cholesterol may be considered
an early risk factor for AD. There is a link between APP
processing, Ab production, and the lipid environment [437,
438]. APP is a type I membrane protein that undergoes
proteolytic cleavage within its ectodomain, followed by
intramembrane cleavage on its C-terminal fragment. These
proteolytic pathways lead to the generation of Ab, and both
processes involve proteolytic enzymes known as secretases,
as previously explained. The intramembrane cleavage site
of the APP depends on the length of its transmembrane
domain [439], while membrane composition and its physical
state modulate the ratio between the APP derivatives Ab1
42 and Ab140 [440]. Ab142 is more pathogenic than Ab140
as described earlier in this review. The cleavage of APP may
occur at the exact center of the lipid bilayer [441] where
cholesterol may enhance c-secretase-mediated Ab produc185

Rosales-Corral et al.
tion [442, 443] and, reciprocally, Ab aggregates preferentially bind cholesterol within the lipidic rafts [444]. Thus, a
drastic reduction in membrane cholesterol may result in
decreased amyloid production [442, 443]. On the contrary,
it has also been shown that neuronal membrane cholesterol
loss may enhance amyloid peptide generation [445], which
calls into question the population-based studies which have
demonstrated that cholesterol is an early risk factor for the
development of amyloid pathology [446].
Sphingomyelin (SM), another particularly signicant
lipid in signal transduction, when it accumulates, provides
a favorable milieu for GM1 ganglioside-induced assembly
of Ab-protein [447]. According to Grimm et al. [438], while
the control of cholesterol and SM metabolism involves APP
processing via regulation of the activity of the c-secretase
enzyme, Ab directly activates neutral sphingomyelinase, the
enzyme responsible for metabolizing SM to phosphocholine
and ceramide and downregulates SM levels or reduces de
novo cholesterol synthesis by inhibiting the hydroxymethylglutaryl-CoA reductase (HMGR) activity. Thus, Ab
becomes a cholesterol and sphingomyelin regulator, while
cholesterol and glycosphingolipids may elevate Ab production and SM may reduce Ab production by inhibition of
c-secretase [438]. This is particularly true in individuals
carrying the ApoE4 genotype, because this isoform binds
more avidly to Ab [448] (Fig. 11).

Other important relationships between lipids and AD

involve the polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA, 22:6x-3) and arachidonic acid (AA, 20:4x-6), a precursor in the production of
eicosanoids. Arachidonic acid is a well-known neuroinammation by-product, delivered from cellular membranes
by phospholipases A2, cyclooxygenases, and lipoxygenases
under the eect of cytokines and chemokines once the
proinammatory response to injury is established [164].
This is particularly true in the AD brain [449, 450].
Importantly, AD is associated with depletion of DHA in
the brain [451, 452]. DHA comprises about 40% of the
PUFAs in the brain [453], it is found predominantly in
neuronal membranes in the gray matter, and it has an
important role in cholinergic stimulated signal transduction
at the synapse and phospholipid-mediated signal transduction involving activation of phospholipase A2 and/or PLC
[454]. In fact, regional gray matter volumes in the anterior
cingulate cortex, amygdala, and hippocampus, calculated
using optimized voxel-based morphometry on high-resolution structural magnetic resonance images in adult humans,
revealed a positive association between long-chain omega-3
fatty acid intake and corticolimbic gray matter increase in
volume [455]. There is experimental evidence supporting the
role of DHA in the formation of new memories; for
example, in sh oil-decient rats tested for learning ability

Fig. 11. Cholesterol may interfere with a-secretase activity or may enhance c-secretase (cs) activity, favoring the amyloidogenic pathway;
also, it is possible that cholesterol contributes by relocalizing APP near to the b-secretase (bs) inuence. Ab, correspondingly, aects
cholesterol inux and eux because of its ability to bind cholesterol transporters, while it inhibits cholesterol esterication. Sphingomyelin,
which makes up about 10% of the lipids of brain, has been related to c-secretase (cs) activity and the amyloidogenic pathway. Ab for its part
may induce apoptosis by activating the cPLA2-dependent sphingomyelinaseceramide pathway, which is a phenomenon related to caspase 3
activation, PI3K/Akt inhibition, and arachidonic acid release. Melatonins role (red crosses) in this hypothesis is related to the following: (1)
functional stability of the membrane by avoiding the lipid peroxidation cascade, (2) interfering with lipid-derived proinammatory signals,
(3) it is also possible that melatonin may interfere with PLA2 activity, (4) melatonin reduces cholesterol absorption or augments endogenous
cholesterol clearance mechanisms, and (5) melatonin may interfere with cholesterol transport as well or directly interact with cholesterol;
even though the eects derived from this possible interaction remain to be claried, it has been demonstrated that melatonin may favor the
displacement of cholesterol from the phospholipid bilayer. Reciprocally, cholesterol might inuence melatonins antioxidant capacity.

186

Alzheimers disease and melatonin

related to reference memory and working memory, chronic
administration of DHA led to an improvement in reference
memory-related learning both in young [456] and in old rats
[457]. The diet-induced increase in brain DHA levels has
been related to enhanced reference and working memory
performance as well [458]. Moreover, DHA may promote
the dierentiation of neural stem cells into neurons by
promoting cell cycle exit and suppressing cell death as
evaluated in neural stem cells obtained from 15.5-day-old
rat embryos [459] probably by regulating basic helixloop
helix transcription factors [460]. Ab oligomer-induced
eects, such as phosphorylation of tau and inactivation of
insulin receptor substrate via c-Jun N-terminal kinase
signaling, may be suppressed by the dietary intake of sh
oil/DHA, and this may be accompanied by improvement in
Y-maze performance, as demonstrated in 3xTg-AD mice
[461].

Melatonins role in the lipid connection

Melatonins utility is attributable in great part to its
amphipathic nature, which allows it to pass easily through
all morphophysiological barriers, and this property involves an active interaction with membrane lipids. The
most widely known eect of melatonin on lipids is to
prevent their peroxidation [14, 462, 463]. In fact, there is an
inverse correlation between melatonin levels and peroxidation of lipids following the intracerebral injection of Ab
[464]. By doing this, melatonin avoids some of the major
problems derived from cell membrane dysfunction and
subsequent neurotoxicity [462, 465]. However, the role of
melatonin seems to be more complex (Fig. 11).
Melatonin may interfere with proinammatory signals by
blocking two principal enzymatic pathways: COX and LOX.
Both of these insert molecular oxygen into molecules of free
and esteried polyunsaturated fatty acids, such as arachidonic acid, and thereby synthesize several dierent biologically active eicosanoids. 12/15-LOX protein levels and
enzyme activity, linked to mechanisms of oxidative stress
and neurodegeneration, have been demonstrated to be
increased in AD brain [466], the same as 5-LOX. This latter
is also known as an active Ab inducer [467], and 5-LOX gene
expression may be suppressed by melatonin through its highanity nuclear receptors, as demonstrated in hippocampus
[468]. It is noted that a drop in melatonin levels, as observed
in elderly subjects with an aging-associated melatonin
deciency, has been related to 5-LOX overexpression [469].
On the contrary, a proradical eect has been described for
melatonin in which it uses these pathways [470], which is a
transitory, early melatonin eect observed in leukocytes,
accompanied by strong liberation of arachidonic acid and
explained as a consequence of calmodulin binding.
Lipid mobilization to obtain polyunsaturated fatty acids
from the membranes for LOX and COX enzymes requires
the intervention of an enzyme, the calcium-dependent
phospholipase A2 (PLA2); melatonin may be a negative
endogenous regulator of cytosolic PLA2 presumably
through a melatonin receptor-mediated process as demonstrated in the rat pineal gland in vitro [471].
Melatonin may also signicantly reduce cholesterol
absorption causing signicant decreases in total cholesterol,

triacylglyceride, very low-density lipoprotein cholesterol,

and low-density lipoprotein cholesterol in plasma and the
concentrations of cholesterol and triacylglyceride in the
liver; this was demonstrated in rats fed on high-cholesterol
diet [472]. In a very particular study (hypercholesterolemic
mice fed with an atherogenic diet), it has reported that
melatonin induces atherosclerotic lesions in the proximal
aorta as a consequence of exacerbated LDL oxidation
[473]. On the contrary, in normolipidemic postmenopausal
women, melatonin has shown to inhibit oxidative modication of low-density lipoprotein particles [474].
The cholesterolmelatonin relationship in the biological
membranes is, from a functional point of view, particularly
relevant. Evaluated in dry cholesterol/lecithin mixed
reversed micelles, melatonin is mainly located in and
oriented in the proximity of the polar heads where it
appears to compete with cholesterol for the hydrophilic
binding sites of lecithin; this is particularly true at high
cholesterol concentrations. Thus, free radical displacement
coming from the aqueous compartment to a high concentration of cholesterol could inuence melatonins antioxidant activity. At the same time, the more concentrated
cholesterol is in membranes, the greater the membrane
rigidity. It is speculated that competition with melatonin
may favor the displacement of cholesterol from the
phospholipid bilayer [475]. This feature gains relevance
because decreasing membrane cholesterol in mature neurons may reduce their susceptibility to Ab, tau production,
and cell death, whereas increasing membrane cholesterol in
young neurons enhances the Ab-mediated cellular processes, as demonstrated in hippocampal neurons [476]
(Fig. 11).

Concluding remarks
Is it just a coincidence that while melatonin declines with
age, the probability of experiencing AD grows? New
ndings on CSF ow, possibly moving from the choroid
ssure into the ventricular system, could help to explain
why melatonin is found in higher concentration in the CSF
than in simultaneously sampled blood. Thus, neural tissue
in contact with the ventricular system via hypothetical
choroid plexus portals would have high levels of cellular
melatonin [477]. A CSF deciency of melatonin has been
demonstrated to precede clinical symptoms of AD [22, 265]
and, the loss of this lipophilic antioxidant normally
concentrated in the ventricular CSF exposes highly active
and vulnerable brain tissue to self-generated oxygen radicals.
Melatonins more common indication in patients with
AD is sleep regulation because sleep disruptions, nightly
restlessness, and sundowning are frequently observed in
elderly and particularly in patients with AD [44]. This is
related to decreased levels of both melatonin [415] and
melatonin receptors in the SCN [478]. It has also a potential
to treat mood disorders [30, 43], commonly associated with
AD [28, 30].
By taking into account the most compelling hypotheses
trying to explain the cellular and biomolecular alterations
in Alzheimers disease, however, a growing body of
evidence supports the protective role of melatonin, exceed187

Rosales-Corral et al.
ing the above-mentioned conventional uses. Thus, melatonin has a role in each of the dierent reviewed hypotheses:
(i) it prevents amyloid overproduction, (ii) it reduces
hyperphosphorylation of tau [15, 166], (iii) it is an antioxidant and free radical scavenger, (iv) it modulates proinammatory processes, (v) it works well as an
anticholinesterase agent, (vi) it prevents mitochondrial
damage and the apoptotic phenomena related with AD,
(vii) it may impair calcium-dependent toxicity, (viii) it
reduces insulin resistance as well as glucose transport, and
nally (ix) it is able to maintain the integrity and functionality of cellular membranes, thanks to its ability to interact
with lipids or against their neuroinammatory or proapoptotic signals when the lipid balance becomes aected.
The functional translation of these biomolecular eects
has been also well documented. MT2 receptor-decient
mice undergo impairment of synaptic plasticity and learning-dependent behavior, suggesting that MT2 receptors
participate in hippocampal synaptic plasticity and in
memory processes [299]. Also relevant are the protective
eects of melatonin on cognition in a variety of tasks of
working memory, spatial reference learning/memory, and
basic mnemonic function, as observed in a transgenic model
of AD [20]. It is worth remembering the increased melatonin 1a-receptor immunoreactivity in the hippocampus of
patients with AD, which may be a compensatory response
to impaired melatonin levels [417].
It is also true that in transgenic animals, additionally
exposed to aluminum for months (aluminum has been
circumstantially linked to AD [16, 479, 480]), melatonin did
not ameliorate the behavioral eects [21] even though they
did respond well to the antioxidant actions of [92]. Limited
or even null results in memory performance or other high
mental functions using melatonin have been observed in
some clinical trials [11]. However, these changes are
associated with the loss of brain cells. The greater the loss
of brain cells, the more severe the deterioration in high
mental functions, and no drug exists that is capable of
regenerating lost neurons. Once the brain tissue has
degenerated, there is just a little chance of recovering [176].
There are several concerns about melatonin. From a
cellular, basic perspective, we nd a single report where
melatonin reportedly worsens the neurodegenerative
pathology. It is a rotenone-induced Parkinsons diseasespecic model, where melatonin not only failed to impair
neuronal degeneration but potentiated neurodegeneration
[19]. However, synergistic eects of melatonin against
MPTP-induced mitochondrial damage and dopamine
depletion have been also reported [481]. Otherwise, the
evidence indicating the protective role of melatonin on
mitochondria within CNS is vast [239, 342346, 348350,
352, 353, 355, 359].
On the other hand, there are several clinical concerns.
One refers to dose and side eects. In a few isolated studies,
melatonin has been related to sleepiness, dizziness, headaches, nightmares, confusion, sleepwalking, daytime sleepiness, and abdominal discomfort, even though some results
deserve a re-analysis. For example, using a high dose of
melatonin (20 mg/kg) in mice undergoing electroconvulsive
stimulation, a strong long-term memory decit was attributed to melatonin [482]. However, it was not clear what
188

caused the memory impairment actually, because the

electroconvulsive stimulation has been often related to
memory impairment by itself; and not only in rodents but
in humans (reviewed in [483]). On the other hand, not in
rats but in epileptic children, a randomized, double-blind,
placebo-controlled trial demonstrated that melatonin improved cognitive and social function as well as emotional
well-being and behavior [484]. It has been also reported that
ramelteon, a synthetic melatonin derivative, administrated
prior to a short (2 hr) evening nap, impairs signicantly
neurobehavioral performance for up to 12 hr after awakening [485].However, a 2-hr nap is not a short nap; naps
longer than 30 min have been largely associated with a loss
of productivity and sleep inertia [486]. Thus, probably
ramelteon was not responsible for a low neurobehavioral
performance, but the long nap by itself.
Melatonin doses ranging from 3 to 6.6 g/day for more
than 30 days were administrated in patients with Parkinsons disease, and the number of collateral eects, such as
headache, somnolence, or abdominal cramps, were isolated,
with melatonin being remarkably well tolerated [487].
More severe collateral eects have never been observed. In
fact, doses up to 800 mg/kg failed to produce death in mice
[488]; indeed, no lethal dose of melatonin has been
established overall; melatonin has been repeatedly shown,
at any dose to be free of signicant side eects.
Other concerns go in the opposite direction: melatonins
extremely short half-life in the circulation, a question that
have led to the development of synthetic melatonergic drugs
with substantially longer half-life than melatonin [489]. It
should be noted however that the short half-time of
melatonin in the blood does not necessarily translate into
a short half-life within the cells.
This review underlines the potential of melatonin to slow
the progressive deterioration of AD brain, in light of the
known hypotheses that attempt to explain the neurodegeneration. As observed in AD models and based on a
multitude of experimental results, melatonin benets may
well stem from actions that exceed its well-known antioxidant properties. Unfortunately, while there are a number
of well-founded hypotheses, the real cause of neurodegeneration in AD is still unknown. Very likely, there are many
contributing causes to this highly complex disease.

Acknowledgements
A. Coto-Montes is an associate professor at Universidad de
Oviedo (Spain). Jose A. Boga is a researcher of HUCA/
FICYT (Oviedo, Spain). His stay at UTHSCSA has been
subsidized by Instituto de Salud Carlos III (Madrid, Spain).

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