Garbage Truck of the Brain

Maiken Nedergaard
Science 340, 1529 (2013);
DOI: 10.1126/science.1240514

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NEUROSCIENCE
Garbage Truck of the Brain
Maiken Nedergaard
E
ssentially all neurodegenerative dis-
eases are associated with misaccumu-
lation of cellular waste products. Of
these, misfolded or hyperphosphorylated pro-
teins are among the most difficult for the brain
to dispose. For example, tau and β-amyloid
can accumulate as stable aggregates that are
neurotoxic in conditions such as Alzheimer’s
disease (1). Intracellular proteasomal degra-
dation and autophagy are considered the prin-
cipal means for removing proteins in the cen-
tral nervous system, and the dysfunction of
each has been causally associated with neuro-
degeneration (2).Yet many cytosolic proteins
are released into the interstitial space in the
brain, suggesting that extracellular disposal
routes may also eliminate waste (3).
Throughout the body’s tissues, bulk flow
of the fluid between cells, into the blood or
lymph, plays an important role in the removal
of potentially toxic metabolic by-products.
Lymphatic vessels, which run in parallel with
the blood vascular system, are the principal
means by which tissues eliminate excess
fluid and proteins. Although the density of
lymph vessels generally correlates with tis-
sue metabolic rate (4), the brain and spinal
cord are curiously devoid of such a lymphatic
tree. This is puzzling because the high met-
abolic activity of neurons predicts the need
for rapid elimination of their metabolic by-
products. It was long thought that movement
of the cerebrospinal fluid (CSF), which is
produced in the choroid plexus of the brain
and flows through its ventricles and basal cis-
terns, constitutes a “sink” for waste products
to diffuse from the brain, for eventual clear-
ance to the general circulation. However, the
large tissue distances in most of the brain pre-
vent diffusion and bulk flow from making
this process efficient. Albumin, for instance,
would require more than 100 hours to diffuse
through 1 cm of brain tissue (5).
Two-photon imaging of live mice through
a closed cranial window has since permit-
ted the direct observation of CSF move-
ment through the intact brain. This tech-
nique revealed that CSF is exchanged rap-
CREDIT: K. SUTLIFF/SCIENCE
idly with interstitial fluid (ISF) in the brain
by a highly organized, brain-wide pathway
School of Medicine and Dentistry, University of Rochester
Medical Center, Rochester, NY 14642, USA. E-mail:
nedergaard@urmc.rochester.edu
www.sciencemag.org SCIENCE VOL 340 28 JUNE 2013
Para-arterial
CSF influx
Neuron
Para-
arterial
space
Artery C onvec t i v e flow
AQP4
Astrocyte
vascular ISF
S
ISF
endfeet
Go with the flow. Convective glymphatic fluxes of CSF and ISF propel the waste products of neuron metabo-
lism into the paravenous space, from which they are directed into lymphatic vessels and ultimately return to
the general circulation for clearance by the kidney and liver.
that consists of three serial elements: a para-
arterial CSF influx route, a paravenous ISF
clearance route, and an intracellular trans-
astrocytic path that couples the two extra-
cellular paravascular routes (6). Specifically,
CSF passes through the para-arterial space
that surrounds arteries; the space is bound
by the abluminal surface of the blood vessel
and the apical processes of astrocytes. Water
channels called aquaporin 4 (AQP4) on the
vascular endfeet of astrocytes (7) facilitate
convective flow out of the para-arterial space
and into the interstitial space (see the fig-
ure). As CSF exchanges with the ISF, vec-
torial convective fluxes drive waste products
away from the arteries and toward the veins.
ISF and its constituents then enter the para-
venous space. As ISF exits the brain through
the paravenous route, it reaches lymphatic
vessels in the neck, and eventually returns its
contents to the systemic circulation. Radio-
label tracer studies indicate that 40 to 80% of
large proteins and solutes are removed from
the brain through this macroscopic clearance
pathway (6). CSF can also exit through the
arachnoid villi, which extend through the
outer protective membrane layer of the brain
and allow CSF to exit to the bloodstream, as
well as at sites along the cavity and cranio-
spinal nerve roots. Regardless of the route,
its solutes and proteins ultimately reach the
liver, where they are degraded. As such, the
“glymphatic system”—so-named for its
dependence on glial water channels and its
Published by AAAS
PERSPECTIVES
An intercellular “glymphatic” pathway clears
cell waste from the brain and may reveal
new targets for treating neurodegenerative
diseases.
Skull
Subarachnoid space
Vein
Para-
Waste
Waste venous
efflux
adoption of a clearance function similar to
that of the peripheral lymphatic system—
avoids the need for local protein processing
and degradation. Instead, it facilitates trans-
port to the same central excretion and recy-
cling sites used by other tissues.
Studies of mice genetically engineered to
lack AQP4 showed that fluid flux through the
glymphatic pathway relies on specific expres-
sion of this water channel along the apical
membrane of vascular endfeet of astrocytes
(6). When AQP4 is mislocated to the cell body
of astrocytes or to astrocytic processes that do
not abut the vasculature, as observed in trau-
matic brain injury or stroke (8, 9), clearance
of soluble proteins through the glymphatic
system declines substantially.
An interesting question is whether the
glymphatic system plays a role in spreading
fibrillary tau aggregates through the intersti-
tial space in neurodegenerative disease. The
injection of brain extracts from mice contain-
ing an aggregation-prone form of human tau
protein, into the brains of mice expressing
wild-type human tau, induces self-assembly
of the wild-type human tau into filaments.
This results in the pathological spread of tau
aggregates from the injection site to distant
brain regions (2, 3, 10).
Perhaps the most persuasive example of
CSF recycling as the cause of dispersing the
initial seeds of tau tangles is after traumatic
brain injury. As a result of axon damage, the
tau concentration in CSF increases by as much
1529
 PERSPECTIVES

as a factor of 40,000 (11). Consequently, as
the heavily tau-laden CSF enters the brain tis-
sue through the para-arterial space, it is taken
up by cells closest to the paravascular bound-
ary, thereby generating the typical paravascu-
lar predominance of tau-immunoreactive neu-
rofibrillary tangles (12). Similarly, glymphatic
CSF influx may also act as a constant source
for delivering β-amyloid, which could con-
tribute to the growth of para-arterial deposits
in cerebral amyloid angiopathy. In turn, the
same para-arterial space that normally func-
tions as a low-resistance influx path for CSF
will narrow as the amyloid plaques enlarge,
slowing glymphatic clearance and thus accel-
erating amyloid deposition (13).
As such, studies of the multiple pathways
involved in glymphatic clearance may iden-
tify new targets for treating neurodegenerative
diseases. For example, mislocation of AQP4
water channels may contribute to neuro-
degenerative disease progression. Thus,
potentiating the insertion and activity of AQP4
channels in astrocytic vascular endfeet might
mitigate or even reverse the course of protein-
associated neurodegenerative disorders.
Can the efficiency of glymphatic clear-
ance be assessed? Preclinical analysis in rats
shows that magnetic resonance imaging can
provide a brain-wide map of both glymphatic
influx and efflux, by which clearance kinet-
ics can be derived and compared across sub-
jects (14, 15). By extending this approach
to humans, it may be possible to identify
patients at risk for developing Alzheimer’s
disease who would benefit from therapeu-
tic intervention before symptomatic neuro-
degeneration ensues. Similarly, this type of
analysis might allow the monitoring of treat-
ment responses, as well as the identification
of genetic markers that predict enhanced sus-
ceptibility to glymphatic decline. Such an
approach also may be suitable for victims of
brain injury who develop chronic traumatic
encephalopathy, which is characterized by
paravascular tau tangles and premature neu-
ronal degeneration (12). There are currently
no definitive diagnostics that identify suscep-
tible individuals, and thus no means by which
to achieve early clinical intervention. Recog-
nition that the brain, like all other organs, uses
both local and organ-wide mechanisms for
clearing interstitial protein waste may offer
new insights into the pathophysiology and
prophylaxis of neurodegeneration, as well
as injuries and proteinopathies of the human
central nervous system..
References
1. L. Mucke, D. J. Selkoe, Cold Spring Harb. Perspect. Med.
2, a006338 (2012).
2. B. Frost, M. I. Diamond, Nat. Rev. Neurosci. 11, 155
(2010).
3. L. C. Walker, M. I. Diamond, K. E. Duff, B. T. Hyman, J.
Am. Med. Assoc. Neurol. 70, 304 (2013).
4. M. Loukas et al., Clin. Anat. 24, 807 (2011).
5. H. F. Cserr, Physiol. Rev. 51, 273 (1971).
6. J. J. Iliff et al., Sci. Transl. Med. 4, 147ra111 (2012).
7. E. A. Nagelhus, T. M. Mathiisen, O. P. Ottersen, Neurosci-
ence 129, 905 (2004).
8. J. J. Iliff, M. Nedergaard, Stroke 44, (Suppl 1), S93
(2013).
9. Z. Ren et al., J. Cereb. Blood Flow Metab. 33, 834
(2013).
10. F. Clavaguera et al., Nat. Cell Biol. 11, 909 (2009).
11. F. P. Zemlan et al., Brain Res. 947, 131 (2002).
12. L. E. Goldstein et al., Sci. Transl. Med.4, 134ra60 (2012).
13. R. O. Weller, S. D. Preston, M. Subash, R. O. Carare,
Alzheimers Res. Ther. 1, 6 (2009).
14. J. J. Iliff et al., J. Clin. Invest. 123, 1299 (2013).
15. L. Yang et al., J. Transl. Med. 11, 107 (2013).
10.1126/science.1240514

CHEMISTRY

More Can Be Better in N2 Activation A soluble trititanium hydride cluster cleaves

molecular nitrogen and forms N-H bonds.

Michael D. Fryzuk

N
itrogen is essential for life, but only
a few organisms can convert the
abundant dinitrogen (N2) molecules
from the air into chemically usable forms of
nitrogen. The Haber-Bosch process, devel-
oped over 100 years ago (1), combines N2
and H2 gases over activated iron surfaces to
generate ammonia (NH3) for use as fertilizer
or to produce other chemicals, but this pro-
cess is extremely energy intensive. Chemists
have long searched for a low-energy process
that converts N2 to ammonia or higher-value
nitrogen compounds such as N-heterocycles
or amines. However, the intrinsic inertness of
N2 has made it challenging to discover metal
complexes that can both bind and activate
it. On page 1549, Shima et al. report a triti-
tanium hydride cluster that cleaves N2 and
functionalizes it to form N-H bonds (2).
Since the discovery of the first dinitro-
gen complex [Ru(NH3)5N2]2+ in 1965, many
decades of research have been invested in
Department of Chemistry, The University of British Colum-
bia, Vancouver, BC, Canada, V6T1Z1. E-mail: fryzuk@
chem.ubc.ca
the search for soluble complexes that bind, the dinitrogen unit was only slightly acti-
activate, and functionalize N2 (3). Generally, vated upon coordination. A more recent
coordination of N2 to a single metal center study showed that ditantalum tetrahydride
can result in mild activation, as determined complex can activate N2 but cannot cleave
by an increase in bond length or a decrease the very strong N-N triple bond (5). A dini-
in stretching frequency from free N2. Higher obium tetrahydride complex has since been
levels of activation have been found when N2 reported to cleave N2 completely to generate
binds to two or more metal centers. a diniobium dinitride species, but without
The ability of hydride complexes to bind N-H bond formation (6). This work showed
dinitrogen with loss of H2 has been known that N2 could be activated by elimination of
since the late 1960s (4). In these early cases, H2, which is a source of two electrons for
H Ti H Ti H Ti H
H H H H N N
N2 N2
H N N
Ti Ti (–2 H2) Ti Ti ∆ Ti Ti
H N N
H
H H
Cp’3Ti3H7 (Cp’ = C5Me4SiMe3) Cp’3Ti3N2H3 Cp’3Ti3N4H3
1 2 3
How N2 is caught and converted. Shima et al. show that trititanium heptahydride 1 can activate molecular
nitrogen to generate trititanium imide-nitride 2. The latter can further react with more N2 to produce the
trititanium triimide-nitride 3. Both processes are unprecedented and will guide future studies in N2 activation.
Cp⬘, tetramethyl(trimethylsilyl)cyclopentadienyl.

1530 28 JUNE 2013 VOL 340 SCIENCE www.sciencemag.org

Published by AAAS