A Brief Survey of Three Diseases Associated with Defective Programmed Cell

Death Pathways

By Victor Gardner
AP Biology, Periods 6-7

Submitted to: Dr. Madu

Date of Submission: 19 October 2014

Abstract
Malfunctioning apoptosis has been implicated in several diseases, including the range of
immunodeficiencies caused by HIV, Alzheimer's disease and dementia, and even psychological depression. The
present review attempts to provide a brief overview of the clinical manifestations of, role of apoptosis in, and
treatments that affect apoptosis or effect cellular regeneration for each disease. In HIV, such treatments include
those which inhibit HIV protease; in Alzheimer's, treatments focus on inhibiting the effects of
hyperphosphorylation generated by GSK3; in depression, focus is made on the regeneration of hippocampal tissue
lost to apoptosis. Present research in the treatment of each disease is then considered, and a full list of citations is
provided.

1. Introduction
Apoptosis, programmed cell death, is essential to regulating the activities of cells in multicellular organisms. For
example, the eukaryotic cells that make up multicellular organisms need signals not only to grow and proliferate, but to
merely survive. Cells that do not receive enough of such survival factors die off through apoptosis. An example of such
behavior is found in nerve cells: in the developing nervous system, nerve cells are produced in excess; however, those that
do not receive enough survival factor die out, leaving only those cells required by the organism [1].
Just as cell-survival factors exist, so do cell-death factors. The best understood of these cell-death factors is
TGF-. TGF- binds to cell-surface receptors, initiating a signal transduction pathway that results in several changes in
gene expression, ultimately resulting in cell death [1].
It is well understood that gene expression can affect the life-or-death status of a cell. For example, several genes
have been termed oncogenes for their roles in coding for proteins that inhibit apoptosis and thereby promote cancer
generation. Gene expression is, by extension, controlled by several transcription factors, such as those in the NFkB
family. This family of transcription factors serves to induce the expression of several genes which produce proteins that
inhibit apoptosis, such as the caspase-8 antagonist FLIP [2].
Other such inhibitors of apoptosis include the family of Inhibitor of Apoptosis Proteins (IAP), which serve to
inhibit proapoptotic caspases, which are themselves essentially proteases that induce cell death. IAPs inhibit caspase
activity through direct binding to activated caspases; for example, the apoptosis-initiator caspase-9 is directly suppressed
through the activity of ML-IAP. Every IAP contains at least one copy of the baculovirus iap repeat (BIR) domain; it is this
domain that most directly partakes in the inhibitory activities of IAPs. IAPs are highly selective in their inhibitory
prowess, unlike certain virus proteins, and so can only inhibit certain apoptotic pathways, but not others [3].
Most pathways for apoptosis operate through activating such caspases. For example, some of the pathways
moderated by Tumor Necrosis Factor (TNF) contain a "Death Domain." Ligation of this Death Domain results in the
activation of certain intracellular proteins, eventually activating the caspases [52]. By extension, certain caspases operate
through affecting the structural integrity of the mitochondrial membrane. One the outer membrane of the mitochondria is
compromised, cytochrome-c, normally used in cellular respiration, leaks out. Cytochrome-c then proceeds to aid in the
assembly of a multiprotein complex known as the apoptosome, which itself proceeds to effect apoptosis in the cell [4].
In the present work, the role of apoptosis in three disease, HIV, Alzheimer's disease, and depression, is
considered. First, a general overview of the causes and clinical manifestations of each disease is provided. This overview
is then followed by a discussion of the role of apoptosis in the manifestation of the disease. Finally, a survey of treatment
options that either affect apoptosis or affect the loss of cells due to apoptosis is made. The article closes with a more
general discussion of treatment options involving apoptosis, and a list of references is provided.

2. Human Immunodeficiency Virus (HIV)

(a) A Brief Description of the Human Immunodeficiency Virus
Human immunodeficiency Virus, otherwise known as HIV, is a retrovirus (an enveloped virus replicating in a
host cell via reverse transcription, the process of creating DNA from an RNA template) of the family lentiviridae (a genus
of viruses in the family Retroviridae characterized by its long gestation period) [5]. The virus itself consists of the capsid,
formed from a set of viral proteins themselves surrounding two RNA copies of the viral genome, surrounded by the viral
envelope, which contains several glycoproteins that enable the virus to bind to specific receptors on the target cell. After
binding to the host cell, the HIV viral envelope fuses with the plasma membrane, releasing the capsid into the cytosol. The
capsid proceeds to release its viral RNA into the cytosol, which, due to the virus's enzyme reverse transcriptase, form
double-stranded DNA. This DNA effects the synthesis of a new HIV, which leaves the cell, surrounded by a viral
envelope converted from the plasma membrane, infect more cells [5]. Moreover, the virus has been shown to neutralize
host restriction factors such as Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3g (A3G) using HIV-1
viral infectivity factor (ViF), making the search for treatments for this disease difficult, to say the least [6].
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HIV infection is often associated with extreme viraemia (the presence of viruses in the bloodstream), with virus
level often exceeding 5 million viral particles per milliliter of blood [7]. Furthermore, in the absence of antiretroviral
therapy, this viral load leads to CD4+ T-cell (a form of white blood cell) depletion and the resultant disease progression to
acquired immune deficiency syndrome (AIDS, the worst symptomatic manifestation of HIV) [7, 8].
The symptoms directly manifested by HIV include swollen glands in the throat, armpit, or groin, a slight fever,
headaches, fever, and muscle aches; there are usually no symptoms for years after infection. In the most advanced stage of
the disease, AIDS, symptoms include thrush (a yeast infection of the mouth), severe and recurrent vaginal yeast
infections, periods of extreme tiredness, frequent diarrhea, and persistent confusion [9]. In addition to these physical
manifestations of HIV, several psychological factors come into play for people living with the disease. For example,
cultural stigma surrounding AIDS often impairs prevention, diagnosis, and treatment of the disease, in addition to being
difficult to measure properly (although several tests, such as the Berger HIV stigma scale, have attempted to validly
measure the psychometrics of HIV stigma) [10, 11]. Furthermore, the high rate of depression in HIV-positive patients has
resulted in a plethora of truncated treatment regimens and, by extension, deaths [12].
Finally, on account of being a disease that weakens the immune system, HIV is associated with a high degree of
comorbidity [13]. For example, toxoplasmic encephalitis, an infectious disease caused by the single-celled protozoan
Toxoplasm a gondii that results in muscle pains and fever, frequently occurs in HIV patients [14]. Moreover, highly active
retroviral therapy, a treatment for HIV, has been shown to correlate with higher instances of HIV-1 associated
neurocognitive disorder [15].
(b) The Role of Apoptosis in Infections of the Human Immunodeficiency Virus
As mentioned earlier, HIV results in a lessened ability for the host's immune system to respond to pathogens,
resulting in possibly deadly comorbidity in addition to complications from HIV itself. HIV effects this immune-systemsub-functioning partly through induced apoptosis in CD4+ and CD8+ T-cells, literally reducing the number of lymphocytes
that can respond to any given infection [16, 17]. Such T-cells infected with HIV show changes in the regulation of the
apoptotic regulator FasL, a transmembrane protein that, upon binding with its ligand, induces apoptosis. These changes,
such as an increase in apoptosis-inducing BclXS and Bax coupled with a
decrease in apoptosis-preventing Bcl2 and BclXL, cause an enhanced propensity
towards apoptosis in the affected T-cells [17].
HIV induces apoptosis in T-cells through other methods as well. For
example, upon finding out it has HIV, the body's response is to produce anti
HIV circulating immune complexes (CIC-HIV+). These CIC-HIV+ consist of the
anti-HIV antibody anti-gp120 and HIV antigen. Ligation of CD4+ lymphocytes
by CIC-HIV+ induces apoptosis in the lymphocytes, further progressing the
disease's namesake immunodeficiency [18]. Moreover, the apoptosis-inducing
model of HIV is supported by tests performed upon primates. In giving HIV to
chimpanzees, Davis et al. found that apoptosis levels of CD4+ cells increased
dramatically in the experimental group and not at all in the controls group.
Furthermore, these results were correlated with immune system overreaction,
supporting the CIC-HIV+ model described previously in this paragraph [19].
While apoptosis can in fact be a response to the activation of a T-cell receptor
for antigen, in immature thymocytes (progenitors to cells present in the thymus,
a lymphoid organ, part of the immune system, present in the back on the neck)
the process is rather signaled through the lack of certain signals essential to the
Figure 1: Image copied and modified cell's continuation of life [20].
HIV also decreases the amount of Interleukin 2 (IL-2, a cytokine
from [3]. In this case, the
signaling
molecule essential to the operation of the immune system) and Tumor
measurement of RNA molecules was
Necrosis
Factor
(TNF-, a cytokine involved in the acute phase reaction, an
a way of determining the number of
immune
system
response
that causes a change in the concentration of various
HIV viruses present (i.e. the RNA
proteins) produced by cells in the infected person. This occurs because these
molecules belonged to HIV viruses).
cytokines are themselves produced by macrophages destroyed by HIV [21].
600-1200mg ABT-538 was taken
(c) Advancements in the Treatment of the Human Immunodeficiency Virus
orally daily beginning on day 1, and
Due to the reliance of the human immunodeficiency virus upon
subject viraemia was monitored
apoptosis
to spread disease, recent advances have been made in the treatment of
thereafter.
HIV based on medicines designed to inhibit the efficacy of the virus's
apoptosis-mechanisms. For example, a medicine, ABT-538, takes advantage of the fact that HIV utilize the enzyme HIV2

1 protease in causing a cell's apoptosis by inhibiting the function of that enzyme. HIV-1 protease functions either by
eliminating the integrity of the mitochondrial membrane, causing apoptosis-inducing enzymes such as cytochrome c to be
released from the mitochondria, or by its own interaction with the gene breast carcinoma-associated protein 3(BCA3),
which increases the production of the protein Bax, which itself play a role in signaling apoptosis [22]. ABT-538 acts as a
symmetrical inhibitor of HIV-1 protease, effectively blocking out signals for the cell to perform apoptosis. In addition, the
molecule acts as an "optimal compromise between oral viability and potency," meaning that it can be ingested orally
while still maintaining a high efficacy as an anti-HIV medication [23]. ABT-538 does not, however, act on cells already
infected with the virus; rather, it prevents new infections. Thus, the decrease in viraemia observed is effected by those
already-infected cells dying out and no new cells taking their place, essentially "starving" the virus population [8]. Figure
1 shows the number of HIV RNA molecules per mL measured in a study where subjects were given ABT-538. Moreover,
on account of a lessening concentration of HIV viruses causing apoptosis of lymphocytes, white blood cell counts in
patients treated with ABT-538 rise significantly [8] It should be noted, however, that a different study found that some
individuals reach a "plateau" in the recovery of CD4+ lymphocytes, bringing into question the extent of this medication's
effectivity [24].
Another potential medicine, A-77003, also works by inhibiting HIV-protease. An in vitro study, however,
revealed mixed results. On the one hand, when certain concentrations (0.5M) are given in continuous infusion to the in
vitro cells, the spread of HIV throughout the culture is severely limited, even for 72 hours after the truncation of A-77003
supply; on the other hand, when 1mg a1 acid glycoprotein was added to the culture, the efficacy of the medication was
ablated, bringing into question the potential for clinical applications and in vivo studies [25].

3. Alzheimer's Disease
(a) A Brief Description of Alzheimer's Disease
Alzheimer's disease, the fourth most common cause of death in the United
States, is also the nation's leading cause of dementia (a progressive deterioration
of cognitive function) [26]. It is characterized by neurodegenerative symptoms,
such as : neurofibrillary tangles (NFTs, aggregates of phosphorylated tau proteins,
which stabilize the cell's microtubule array), amyloid core formation (in
Alzheimer's, the aggregation of misfolded amyloid-beta (A) proteins, causing
abnormal interactions of A with the body), and neutritic degeneration (the
degeneration of nerves through neural inflammation) [27, 28]. The structure of
amyloid-beta was determined to consist of a multimeric polypeptide which itself is
made of approximately 40 subunits, 4 kDa each; these subunits are arranged in a
fibre-like structure [29, 30]. Amyloid-beta aggregates share insolubility as a
superficial similarity with scrapie (a disease causing degeneration of the central
nervous system) polypeptides, although no actual structural similarities with
scrapie have been determined. Finally, the amyloid aggregates in Alzheimer's
share the 4 kDa structural subunit with the disease congophilic angiopathy,
Figure 2: Image adapted from [23].
which itself is caused from amyloid deposits in the blood vessels [29].
(a) Normal amyloid-beta plaque
Amyloid-beta deposition is considered to be the primary factors of
formations. (b) Amorphous amyloidAlzheimer's disease, with the aggregations ultimately resulting in cell damage
beta plaque formations. (c) A mixture
(Figure 2, sub) [31]. This position is further supported b the fact that amyloid
of both normal and amorphous
formation (catalyzed by apolipoprotein E and antichymotrypsin) was
amyloid-beta plaque formations; the
demonstrated to impair cognitive ability in mice [31]. However, it is still not
arrow is pointing to an amorphous
formation surrounded by normal plaque know exactly how amyloid-beta aggregation occurs in non-inherited
Alzheimer's disease [31, 32]. Despite this lack of precise knowledge, however,
structures. (d) A close-up of an
there is a consensus around the genetic mutations that cause familial
amorphous amyloid-beta plaque
Alzheimer's disease. The three genes that code for the amyloid precursor
structure composed of interwoven
protein, presenilin 1, and presenilin 2, when mutated, have been shown to result
amyloid-beta fibers.
in the phenotype of Alzheimer's disease [32]. The formation of neurofibrillary
tangles. by contrast, is thought to be a result, rather than a cause, of Alzheimer's; the neurons seem to be using the
phosphorylation of tau proteins as a defensive barrier against amyloid-beta aggregation [32].
The onset of Alzheimer's disease is ultimately initiated years before any evidence of the characteristic dementia
(in this context, it is important to note that "Alzheimer's disease" denotes the entire pathophysiological process underlying
and preceding Alzheimer's, not simply the clinical manifestation of dementia) [33]. Individuals in the preclinical stage of
Alzheimer's include those with specific "biomarkers" for the disease. These biomarkers include an abundance of
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apolipoprotein E 4 and the presence of autosomal dominant (i.e. only needing a copy of a certain gene from one parent to
inherit a disease) genetic mutations [33]. In the clinical stage, a pragmatic evaluation of the ability of a patient to perform
"activities of daily living" adds to the information gained by a mere cognitive-abilities test. In other words, the cognitive
deterioration brought on by dementia in Alzheimer's disease results in a corresponding deterioration in the quality of life
for an individual living with the disease; for example, it becomes difficult to find belongings, travel outside the home, use
the telephone, or even partake in usual hobbies and games [34].
(b) The Role of Apoptosis in Alzheimer's Disease
Like many neurodegenerative diseases, Alzheimer's is marked by excessive neuronal apoptosis. In Alzheimer's
disease specifically, there is an overabundance of the cell-death moderator glycogen synthase kinase-3 (GSK3) [35].
Before surveying the mechanisms by which GSK3 mis-moderates apoptosis in Alzheimer's disease, it is first necessary to
provide an overview of the mechanisms by which GSK3 moderates apoptosis in general.
GSK3 is unique in that it can both inhibit extracellular-initiated apoptosis while encouraging intracellular-initiated
apoptosis. The receptor is itself moderated by phosphorylation of certain amino acids, effecting structural alterations that
either inhibit or enhance activity. For example, the phosphorylation of serine-9 (in GSK3) or serine-21 (in GSK3)
inhibits activity, whereas the phosphorylation of tyrosin-216 (in GSK3) or tyrossine-279 (in GSK3) enhances activity.
Moreover, the activity of GSK3 is indirectly controlled by the phosphorylation state of its substrate. GSK3 overexpression
encourages intracellular-initiated apoptosis through partaking in the disruption of the mitochondria, leading to cell death;
the signal for apoptosis can be triggered by DNA damage, irreversible protein misfolding, or other such factors. By
contrast, GSK3 inhibits extracellular-signaled apoptosis by protecting the cell from TNF-mediated cytotoxicity (i.e. GSK3
stops tumor necrosis factors, a so-called "death receptor," from binding and signaling apoptosis) [36].
Given that the aforementioned overabundance of GSK3 in Alzheimer's disease patients results in excessive
neuronal apoptosis, thereby causing the clinical manifestation of dementia, it is now necessary to survey the methods
through which GSK3 effects the programmed death of so many neurons. It has been shown that amyloid-beta influences
that PI3K-Akt intracellular signaling pathway, inhibiting the phosphorylation of serine-9 or -21 (supra). Because the
phosphorylation of this specific amino acid inhibits GSK3's ability to enhance intracellular apoptosis-signaling pathways,
the inhibition of the phosphorylation of this specific amino acid thereby encourages apoptosis [35]. Co-effected by this
signaling pathway is the activation of apoptosis-promoting capase-3 [37]. This caspase operated by weakening the
structural integrity of the mitochondrial membrane, allowing cytochrome c to leak out, which then promotes the assembly
of apoptosome, an essential protein in the process of apoptosis [38].
(c) Advancements in the Treatment of Alzheimer's Disease
Existing treatments for Alzheimer's disease have proven ineffective, revealing the need for further study into
possible avenues of therapy for treatment[39, 40]. Given that Alzheimer's is caused by both excessive phosphorylation of
various proteins and amyloid-beta toxicity (itself on account of excessive GSK3 activity from the presence of amyloidbeta), it follows that inhibiting the protein kinases implicated in this disease should be the goal of new therapeutic
approaches for treating the disease. On account of evidence that excessive tau protein phosphorylation (i.e. neurofibrillary
tangles) is correlated with high amyloid-beta levels, a path for researching new therapeutic approaches have been
proposed that inhibit the phosphorylation of tau proteins. Such a therapy would target multiple kinases (including GSK3)
implicated in tau phosphorylation, thereby reducing the ability of the cell to phosphorylate aggregates of tau [39].
Several inhibitors act through just such a method. Tideglusib-12 (NP-12), a non-competitive inhibitor of GSK3,
was shown to reduce both tau phosphorylation and amyloid-beta deposition. Moreover, NP-12 acts as an agonist (a
molecule which initiates a physical response through binding to a receptor, i.e. a ligand which activates a specific cellular
response) for PPAP, causing several anti-inflammatory and protective properties to show in neurons [40]. In addition to
NP-12, the NAD+-dependent sirtuin SIRT1 has been implicated in regulation of amyloid-beta generation. However,
researchers have suggested that a calorie-restriction diet could affect SIRT1 in such a way as to mediate excessive
amyloid-beta deposition. More importantly, however, is the fact that SIRT1 in part prevents amyloid-beta deposition
through the inhibition of ROCK1 (rho-associated, coiled-coil-containing protein kinase 1) expression, opening new doors
for research in either ROCK1 inhibitors or SIRT1 enhancers [41]. Finally, the MAPK family of inhibitors shown promise
as an inhibitor of both tau phosphorylation and the degenerative toxicity caused by amyloid-beta [40].

4. Depression
(a) A Brief Description of Depression
Stress is not only ever-present in human culture; it represents an essential alarm system for any individual
organism. Upon an organism's encountering a "threat to homeostasis," whether it be lack of situational information,
perceived loss of control, excessive blood loss, injury, inflammation, or excessive psychosocial demands, that organism
may feel "stressed." In other words, upon encountering any one or more of the aforementioned situations, the organism's
limbic-hypothalamo-pituitary-adrenal (HPA) brain structure, integrating several emotional, cognitive, neuroendocrine (i.e.
hormonal), and autonomic (i.e. subconscious, part of the
peripheral nervous system) pathways, mediates, along with the
sympathico-adrenomedullary system, the production of
corticotropin-releasing hormone (CRH), which in turn induces
the production and release of adrenocorticotroph hormone
from the pituitary gland. Adrenocorticotroph in turn causes the
production and release of glucocorticoids (a form of
corticosteroids) from the adrenal cortex [42, 43]. While under
normal situations this biological response to stress provides an
impetus for the organism to address the source of stress,
prolonged hyperactivity of the HPA and concomitant
corticosteroid overproduction ultimately results in
depression [42-44]. Moreover, in depressive patients the
hippocampus, amygdala, and prefrontal cortex show altered
Figure 3: Image adapted from [42]. In this study,
patterns of activity in PET scans and demonstrate a decrease
patients were asked to perform a "simple task," such as
in volume; it should be noted, however, that amygdala volume
copying a circle or a diamond. These results show that
actually increases after the first episode of depression,
in both reaction time (RT) and motor time (MT),
decreasing in later episodes, as adrenocortical steroids
depressed patients took significantly longer to perform
produce a wide array of effects upon the structure [43].
the same tasks as the controls. The data were recorded
Patients with depression have an increased risk for
using a Calcomp 2300 digitizer linked to a PC; the array
comorbid diseases to arise, further complicating
had been specially designed to measure pen pressure.
treatment [44]. For example, although at first a controversial
An ANOVA was performed to prove the results were
stance, depression has been recognized as an independent risk
significant.
factor for the development of Ischemic heart disease, as
opposed to simply a secondary by-product of feeling sad about having heart problems. Furthermore, it has been shown
that depression in patients with heart disease is an accurate indicator of mortality 6 months after a myocardial infarction
(i.e. a heart attack) [44]. The relationship between sleep and depression, however, is harder to pin down, on account of
several "confounding variables" that must be accounted for in performing studies, such as age (increasing age results in
prolonged sleep latency, an increase in nocturnal awakenings, and pronounced early-morning wakening), gender (slowwave-sleep, i.e. "deep sleep," is reduced in healthy males as compared to healthy females), and severity of depression
(with increasing severity of depression, sleep continuity seems to be impaired). Despite these hurdles, however, it has
been determined that, overall, that patients with depression have REM deprivation, sleep deprivation, and increased sleep
latency (the time it takes to fall asleep) as compared to healthy individuals [45]. A third pronounced symptom of
depression is psychomotor retardation. A study performed by Bernard Sabbe et al. found that for three separate tasks, (1)
copying "simple figures" such as a circle or a diamond, (2) copying "complex figures" such as letter combinations or
unknown patters, and (3) rotating figures, depressed patients presented with both a longer reaction time and a longer
motor-processing time than healthy individuals (Figure 3). The increase in reaction time can be considered revealing of a
retardation of cognitive processing in depressed patients; similarly, the increase in motor-processing time is representative
of a retardation in motor-processing [46].
(b) The Role of Apoptosis in Depression
Evidence has come to light suggesting that depression effects structural changes in certain areas of the brain, even
inducing neural apoptosis. For example, in a study funded by the Sri Lanka Council for Agriculture Research Policy, the
brain of a twenty five year old male who had committed suicide through self-immolation (namely, burning 81% of his
body area) was observed. Researchers found that the subicular region of the man's brain contained apoptotic neurons,
caused by the overstimulation of glucocorticoid receptors on the neurons. Moreover, observed hippocampal apoptosis was
mediated through overstimulation of corticosteroid receptors in the region. It was also proposed that mineralocorticoid
5

receptors were responsible for preventing cell death, possibly acting as a protection from apoptosis-inducing
corticosteroids and glucocorticoids [47].
More evidence for apoptosis in depression was found in studies performed on both rats and tree shrews. In
experiments in which tree shrews were subjected to psychosocial stress for extended periods of time, apoptosis was found
in the hippocampus, along with clear rises in cortisol and reductions in body weight. However, upon magnetic resonance
imaging (MRI), no significant reduction in brain mass was observed. Furthermore, it is also important to note that a large
number of cells could have already died only a short time after the onset of stress, meaning that the researchers could not
observe the initial increased levels of neural apoptosis [42]. In rats, acute short-term stress has been shown to hinder
neurogenesis, with long-term stress initiating apoptosis in the hippocampus. This heightened apoptosis continues
immediately after the removal of stress, but levels out after about three weeks without psychosocial stress [42].
In addition to heightened corticosteroid levels, an overexpression of Bcl-2 proteins congregating in the outer
mitochondrial membrane also plays a role in initiating programmed cell death under stress [48]. As mentioned earlier,
heart attack patients often suffer from severe depression. It has been demonstrated that morbidity may be influenced by
increased levels of programmed cell death in patients suffering from comorbid depression and cardiovascular disease [48].
Moreover, acute depression is associated with heightened apoptosis in peripheral blood lymphocytes, such as natural killer
cells, which results in reduced immune system efficacy [49].
(c) Advancements in the Treatment of Depression
Research into development of new therapies for depression have recently focused on the role of brain-derived
neurotrophic factor (BDNF), a neural growth factor, and its role in the plasticity (i.e. ability to form tissue) of neurons. In
fact, it has been shown that a majority of antidepressants operate through increasing the activity of BDNF and its receptor
TrkB, a tyrosine kinase receptor. Essentially, the stimulation of BDNF and TrkB enhances both nerve growth and neural
plasticity, allowing for the regenesis of tissue and cells lost to excessive apoptosis [50]. Before an overview of how drugs
increase the activity of BDNF, however, it is first necessary to provide an overview of how BDNF and TrkB work.
Upon being stimulated by BDNF, TrkB dimerizes and activates intracellular signal transduction pathways that
ultimately result in the activation of several transcription factors. One such pathway is Phospholipase C (PLC). In this
pathway, the activation of TrkB by BDNF directly activates PLC, which in turn hydrolyzes phosphatidylinositol
4,5-biphosphate, producing the secondary messengers diacyglycerol and inositol 1,4,5-triphosphate (IP3). IP3 then
proceeds to cause the release of Ca2+, more secondary messengers, which ultimately result in nerve growth and tissue
development, replacing that tissue lost to depression-induced apoptosis [51].
Antidepressants utilizing BDNF have been shown to only be effective after multiple treatments; this is likely
because a corresponding increase in neuroregeneration can only be effected after several days of increased BDNF and
TrkB expression; furthermore, there is a need for a growth of neuronal tissue configurations in order to recover from
excessive depression-induced neuronal apoptosis [51]. As a caveat, however, BDNF has poor blood-brain penetration,
making it difficult for the drug to be effective taken conveniently, and, on account of its interaction with p75NTR, can
cause pain. To solve this, researchers have developed small ligands capable of signaling TrkB with more specificity than
BDNF. One such compound is LM22A-4, which restores motor learning after administration, and demonstrates a high
specificity and efficacy in its interaction with TrkB [52].

5. Conclusion & Discussion

In the fight against disease, inhibiting or otherwise countering apoptosis seems to be one of the more successful
strategies for combating certain afflictions. For example, in depression, instead of actively inhibiting cell-death pathways,
researchers have developed the experimental LM22A-1, LM22A-2, LM22A-3, and LM22A-4, which do nothing to inhibit
apoptosis; rather, they act as a cell growth factor and plasticity encourager, encouraging neurons to multiply and form
hippocampal tissues to replace those lost to stress-induced (i.e. caused by corticosteroid overproduction) apoptosis [52]. In
fact, these medicines, as compared to the natural nerve growth factor BDNF, demonstrate a heightened efficacy due to
their ability to penetrate into the brain from the blood stream; this ability is a by-product of the fact that they are nonproteins, and so can better diffuse through biological membranes [52].
Alternatively, in Alzheimer's and HIV, current medical research is focusing on ways to inhibit apoptosis and
therefore stop the progression of the disease in the infected individual. For example, HIV contains the protein HIV
protease, which serves to induce apoptosis in lymphocytes through its interactions with the mitochondrial membrane [22].
Antiretroviral therapy, the leading treatment for HIV, attempts to halt the spread of the virus to new lymphocytes,
essentially starving HIV out [25]. However, this treatment is only effective on individuals without acute HIV, and so
requires early detection of the disease, which, as HIV is a retrovirus, is characteristically difficult to do [24].
Treatment for Alzheimer's disease works in a similar vein. Under current treatments, it is difficult to stop the
spread of Alzheimer's. However, research is currently underway to develop medicines that stop neuronal apoptosis by
6

inhibiting amyloid-beta-plaque-induced overexpression of the tyrosine kinase receptor GSK3. Such research hopes to
prevent the hyperphosphorylation of aggregates of tau proteins, which in turn would prevent neural apoptosis, slowing the
spread of the disease [35]. Such research hopes to provide effective medications not only against Alzheimer's, but even
against less severe forms of dementia, such as mild cognitive impairment (MCI), essentially a lesser form of
Alzheimer's [33].

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