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Garbage Truck of the Brain

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

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PERSPECTIVES
NEUROSCIENCE
An intercellular “glymphatic” pathway clears
cell waste from the brain and may reveal
Garbage Truck of the Brain new targets for treating neurodegenerative
diseases.
Maiken Nedergaard

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

idly with interstitial fluid (ISF) in the brain well as at sites along the cavity and cranio- brain regions (2, 3, 10).
by a highly organized, brain-wide pathway spinal nerve roots. Regardless of the route, Perhaps the most persuasive example of
its solutes and proteins ultimately reach the CSF recycling as the cause of dispersing the
liver, where they are degraded. As such, the initial seeds of tau tangles is after traumatic
School of Medicine and Dentistry, University of Rochester
Medical Center, Rochester, NY 14642, USA. E-mail: “glymphatic system”—so-named for its brain injury. As a result of axon damage, the
nedergaard@urmc.rochester.edu dependence on glial water channels and its tau concentration in CSF increases by as much

www.sciencemag.org SCIENCE VOL 340 28 JUNE 2013 1529


Published by AAAS
PERSPECTIVES

as a factor of 40,000 (11). Consequently, as Can the efficiency of glymphatic clear- clearing interstitial protein waste may offer
the heavily tau-laden CSF enters the brain tis- ance be assessed? Preclinical analysis in rats new insights into the pathophysiology and
sue through the para-arterial space, it is taken shows that magnetic resonance imaging can prophylaxis of neurodegeneration, as well
up by cells closest to the paravascular bound- provide a brain-wide map of both glymphatic as injuries and proteinopathies of the human
ary, thereby generating the typical paravascu- influx and efflux, by which clearance kinet- central nervous system..
lar predominance of tau-immunoreactive neu- ics can be derived and compared across sub-
rofibrillary tangles (12). Similarly, glymphatic jects (14, 15). By extending this approach References
1. L. Mucke, D. J. Selkoe, Cold Spring Harb. Perspect. Med.
CSF influx may also act as a constant source to humans, it may be possible to identify 2, a006338 (2012).
for delivering β-amyloid, which could con- patients at risk for developing Alzheimer’s 2. B. Frost, M. I. Diamond, Nat. Rev. Neurosci. 11, 155
tribute to the growth of para-arterial deposits disease who would benefit from therapeu- (2010).
in cerebral amyloid angiopathy. In turn, the tic intervention before symptomatic neuro- 3. L. C. Walker, M. I. Diamond, K. E. Duff, B. T. Hyman, J.
Am. Med. Assoc. Neurol. 70, 304 (2013).
same para-arterial space that normally func- degeneration ensues. Similarly, this type of 4. M. Loukas et al., Clin. Anat. 24, 807 (2011).
tions as a low-resistance influx path for CSF analysis might allow the monitoring of treat- 5. H. F. Cserr, Physiol. Rev. 51, 273 (1971).
will narrow as the amyloid plaques enlarge, ment responses, as well as the identification 6. J. J. Iliff et al., Sci. Transl. Med. 4, 147ra111 (2012).
slowing glymphatic clearance and thus accel- of genetic markers that predict enhanced sus- 7. E. A. Nagelhus, T. M. Mathiisen, O. P. Ottersen, Neurosci-
ence 129, 905 (2004).
erating amyloid deposition (13). ceptibility to glymphatic decline. Such an 8. J. J. Iliff, M. Nedergaard, Stroke 44, (Suppl 1), S93
As such, studies of the multiple pathways approach also may be suitable for victims of (2013).
involved in glymphatic clearance may iden- brain injury who develop chronic traumatic 9. Z. Ren et al., J. Cereb. Blood Flow Metab. 33, 834
(2013).
tify new targets for treating neurodegenerative encephalopathy, which is characterized by 10. F. Clavaguera et al., Nat. Cell Biol. 11, 909 (2009).
diseases. For example, mislocation of AQP4 paravascular tau tangles and premature neu- 11. F. P. Zemlan et al., Brain Res. 947, 131 (2002).
water channels may contribute to neuro- ronal degeneration (12). There are currently 12. L. E. Goldstein et al., Sci. Transl. Med.4, 134ra60 (2012).
degenerative disease progression. Thus, no definitive diagnostics that identify suscep- 13. R. O. Weller, S. D. Preston, M. Subash, R. O. Carare,
Alzheimers Res. Ther. 1, 6 (2009).
potentiating the insertion and activity of AQP4 tible individuals, and thus no means by which 14. J. J. Iliff et al., J. Clin. Invest. 123, 1299 (2013).
channels in astrocytic vascular endfeet might to achieve early clinical intervention. Recog- 15. L. Yang et al., J. Transl. Med. 11, 107 (2013).
mitigate or even reverse the course of protein- nition that the brain, like all other organs, uses
associated neurodegenerative disorders. both local and organ-wide mechanisms for 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 the search for soluble complexes that bind, the dinitrogen unit was only slightly acti-
a few organisms can convert the activate, and functionalize N2 (3). Generally, vated upon coordination. A more recent
abundant dinitrogen (N2) molecules coordination of N2 to a single metal center study showed that ditantalum tetrahydride
from the air into chemically usable forms of can result in mild activation, as determined complex can activate N2 but cannot cleave
nitrogen. The Haber-Bosch process, devel- by an increase in bond length or a decrease the very strong N-N triple bond (5). A dini-
oped over 100 years ago (1), combines N2 in stretching frequency from free N2. Higher obium tetrahydride complex has since been
and H2 gases over activated iron surfaces to levels of activation have been found when N2 reported to cleave N2 completely to generate
generate ammonia (NH3) for use as fertilizer binds to two or more metal centers. a diniobium dinitride species, but without
or to produce other chemicals, but this pro- The ability of hydride complexes to bind N-H bond formation (6). This work showed
cess is extremely energy intensive. Chemists dinitrogen with loss of H2 has been known that N2 could be activated by elimination of
have long searched for a low-energy process since the late 1960s (4). In these early cases, H2, which is a source of two electrons for
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 H Ti H Ti H Ti H
H H H H N N
complexes that can both bind and activate N2 N2
H N N
it. On page 1549, Shima et al. report a triti- Ti Ti (–2 H2) Ti Ti ∆ Ti Ti
tanium hydride cluster that cleaves N2 and H N N
functionalizes it to form N-H bonds (2). H
H H
Since the discovery of the first dinitro- Cp’3Ti3H7 (Cp’ = C5Me4SiMe3) Cp’3Ti3N2H3 Cp’3Ti3N4H3
gen complex [Ru(NH3)5N2]2+ in 1965, many
1 2 3
decades of research have been invested in
How N2 is caught and converted. Shima et al. show that trititanium heptahydride 1 can activate molecular
Department of Chemistry, The University of British Colum- nitrogen to generate trititanium imide-nitride 2. The latter can further react with more N2 to produce the
bia, Vancouver, BC, Canada, V6T1Z1. E-mail: fryzuk@ trititanium triimide-nitride 3. Both processes are unprecedented and will guide future studies in N2 activation.
chem.ubc.ca Cp⬘, tetramethyl(trimethylsilyl)cyclopentadienyl.

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