Review Article | Published:

Clearance systems in the brain—implications for Alzheimer disease

Nature Reviews Neurology volume 11, pages 457470 (2015) | Download Citation

  • An Erratum to this article was published on 29 March 2016

This article has been updated

Abstract

Accumulation of toxic protein aggregates—amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood–brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

Key points

  • Accumulation of neurotoxic forms of amyloid-β (Aβ) and tau proteins is the pathological hallmark of Alzheimer disease (AD)

  • Excess deposition of Aβ results from an imbalance between its production and clearance; in both early-onset and late-onset forms of AD, Aβ clearance seems already impaired at the prodromal stage

  • Aβ is removed from the brain by various overlapping and interacting clearance systems: degradation, blood–brain barrier (BBB) transport, interstitial fluid (ISF) bulk flow, and cerebrospinal fluid (CSF) absorption into the circulatory and peripheral lymphatic systems

  • Although most extracellular Aβ undergoes BBB clearance, the recently discovered glymphatic pathway seems to be important for Aβ clearance

  • Specific BBB transporters for tau have not been identified, suggesting that clearance of tau is less complex than that of Aβ, and mainly relies on degradation, ISF bulk flow, and CSF absorption

  • Precise understanding of the mechanisms of clearance dysfunction in AD is paramount to develop strategies to reduce excess deposition of neuroxic protein and to halt the related pathological changes

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Change history

  • 29 March 2016

    In the initially published version of this article, Figure 1 had an incomplete credit line. The correct credit line reads: Redrawn from Nedergaard, M. Garbage truck of the brain. Science 340, 1529-1530 (2013). Reprinted with permission from AAAS. This error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors acknowledge the following grants: NIH/NIA/NHLBI AG022374, AG13616, AG12101 and AG008051 (to M.J.d.L.), HL118624 (to R.S.O), HL111724 (to L.G.), AG20245 and AG008051 (to T.W.), and NIH/NINDS NS028642 (to C.N.). K.B. has received funding from the Torsten Söderberg Foundation at the Royal Swedish Academy of Sciences, and H.Z. has received funding from the Swedish Research Council and the Knut and Alice Wallenberg Foundation.

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  1. New York University School of Medicine, 660 First Avenue, New York, NY 10016, USA.

    • Jenna M. Tarasoff-Conway
    • , Els Fieremans
    • , Leon Axel
    •  & Charles Nicholson
  2. University of Southampton, Faculty of Medicine, Institute for Life Sciences, Southampton General Hospital, Southampton Hampshire, SO16 6YD, UK.

    • Roxana O. Carare
  3. New York University School of Medicine, 145 East 32nd Street, New York, NY 10016, USA.

    • Ricardo S. Osorio
    • , Lidia Glodzik
    • , Tracy Butler
    • , Henry Rusinek
    • , Blas Frangione
    • , Thomas Wisniewski
    •  & Mony J. de Leon
  4. Zilkha Neurogenetic Institute at Keck School of Medicine of University of Southern California, 1501 San Pablo Street Los Angeles, CA 90089, USA.

    • Berislav V. Zlokovic
  5. The Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden.

    • Kaj Blennow
    •  & Henrik Zetterberg
  6. Université Paris-Descartes, 12 Rue de l'École de Médecine, 75006 Paris, France.

    • Joël Ménard

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Contributions

M.J.d.L., J.M.T.-C., R.O.C., R.S.O., T.B., H.R., C.N., B.V.Z., K.B., H.Z. and T.W. researched data for article. M.J.d.L., J.M.T.-C., R.O.C., B.V.Z., H.Z. and T.W. wrote the article. M.J.d.L. and J.M.T.-C. provided substantial contributions to discussion of the content. All authors participated in reviewing and editing of the manuscript before submission.

Competing interests

K.B. and H.Z. are co-founders of Brain Biomarker Solutions. The other authors declare no competing interests.

Corresponding author

Correspondence to Mony J. de Leon.

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DOI

https://doi.org/10.1038/nrneurol.2015.119

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