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  • Review Article
  • Published:

Clearance systems in the brain—implications for Alzheimer disease

Nature Reviews Neurology volume 11, pages 457–470 (2015)Cite this article

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An Erratum to this article was published on 29 March 2016

This article has been updated

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

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.

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Figure 1: Perivascular clearance comprises perivascular drainage and glymphatic pathways.
Figure 2: Aβ clearance systems.
Figure 3: Aβ efflux and influx through the BBB.

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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.

References

  1. Reitz, C. & Mayeux, R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem. Pharmacol. 88, 640–651 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Guerreiro, R. & Hardy, J. Genetics of Alzheimer's disease. Neurotherapeutics 11, 732–737 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Karch, C. M., Cruchaga, C. & Goate, A. M. Alzheimer's disease genetics: from the bench to the clinic. Neuron 83, 11–26 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bertram, L. & Tanzi, R. E. The genetics of Alzheimer's disease. Prog. Mol. Biol. Transl. Sci. 107, 79–100 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Kim, D. H. et al. Genetic markers for diagnosis and pathogenesis of Alzheimer's disease. Gene 545, 185–193 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Bruni, A. C., Conidi, M. E. & Bernardi, L. Genetics in degenerative dementia: current status and applicability. Alzheimer Dis. Ass. Disord. 28, 199–205 (2014).

    Article  CAS  Google Scholar 

  7. Selkoe, D. J. Aging, amyloid, and Alzheimer's disease: a perspective in honor of Carl Cotman. Neurochem. Res. 28, 1705–1713 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Zlokovic, B. V., Yamada, S., Holtzman, D., Ghiso, J. & Frangione, B. Clearance of amyloid β-peptide from brain: transport or metabolism? Nat. Med. 6, 718–719 (2000).

    Article  PubMed  Google Scholar 

  10. Potter, R. et al. Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. Sci. Transl. Med. 5, 189ra77 (2013).

    Article  PubMed  CAS  Google Scholar 

  11. Mawuenyega, K. G. et al. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 330, 1774 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Reiman, E. M. et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case–control study. Lancet Neurol. 11, 1048–1056 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alzheimer's Association. 2013 Alzheimer's disease facts and figures. Alzheimers Dement. 9, 208–245 (2013).

  14. Zlokovic, B. V. & Frangione, B. Transport-clearance hypothesis for Alzheimer's disease and potential therapeutic implications. Madame Curie Bioscience Database [online], (2003).

    Google Scholar 

  15. Shibata, M. et al. Clearance of Alzheimer's amyloid-β1–40 peptide from brain by LDL receptor-related protein-1 at the blood–brain barrier. J. Clin. Invest. 106, 1489–1499 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Kress, B. T. et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76, 845–861 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Louveau, A.E. et al. Structural and functional features of central nervous system lymphatic vessels. Nature http://dx.doi.org/10.1038/nature14432.

  19. Wingo, T. S., Lah, J. J., Levey, A. I. & Cutler, D. J. Autosomal recessive causes likely in early-onset Alzheimer disease. Arch. Neurol. 69, 59–64 (2012).

    Article  PubMed  Google Scholar 

  20. Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 280–292 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bishop, N. A., Lu, T. & Yankner, B. A. Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hebert, L. E., Scherr, P. A., Bienias, J. L., Bennett, D. A. & Evans, D. A. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch. Neurol. 60, 1119–1122 (2003).

    Article  PubMed  Google Scholar 

  23. Hetzel, L. 65 Years and Over Population: 2000. Census 2000 Brief (DIANE Publishing, 2008).

    Google Scholar 

  24. Alzheimer's Association. 2012 Alzheimer's disease facts and figures. Alzheimers Dement. 8, 131–168 (2012).

  25. Potter, H. & Wisniewski, T. Apolipoprotein E: essential catalyst of the Alzheimer amyloid cascade. Int. J. Alzheimers Dis. 2012, 489428 (2012).

    PubMed  PubMed Central  Google Scholar 

  26. Raber, J., Huang, Y. & Ashford, J. W. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol. Aging 25, 641–650 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Boutajangout, A. & Wisniewski, T. The innate immune system in Alzheimer's disease. Int. J. Cell Biol. 2013 (2013).

  28. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41, 1088–1093 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Di Marco, L. Y. et al. Modifiable lifestyle factors in dementia: a systematic review of longitudinal observational cohort studies. J. Alzheimers Dis. (2014).

  31. Reitz, C., Brayne, C. & Mayeux, R. Epidemiology of Alzheimer disease. Nat. Rev. Neurol. 7, 137–152 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Barnes, D. E. & Yaffe, K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol. 10, 819–828 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Picchioni, D., Reith, R. M., Nadel, J. L. & Smith, C. B. Sleep, plasticity and the pathophysiology of neurodevelopmental disorders: the potential roles of protein synthesis and other cellular processes. Brain Sci. 4, 150–201 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Ju, Y.-E., Lucey, B. P. & Holtzman, D. M. Sleep and Alzheimer disease pathology—a bidirectional relationship. Nat. Rev. Neurol. 10, 115–119 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Spira, A. P. et al. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 70, 1537–1543 (2013).

    PubMed  PubMed Central  Google Scholar 

  36. Jack, C. R. Jr et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. de Leon, M. J., Bobinski, M., Convit, A. & De Santi, S. in Neurobiology of Mental Illness 1st edn Ch. 5 (eds Charney, D. S. & Nestler E. J.) 698–714 (Oxford University Press, 1999).

    Google Scholar 

  38. Spires-Jones, T. L. & Hyman, B. T. The intersection of amyloid beta and tau at synapses in Alzheimer's disease. Neuron 82, 756–771 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Thal, D. R. et al. Pathology of clinical and preclinical Alzheimer's disease. Eur. Arch. Psychiatry Clin. Neurosci. 263 (Suppl. 2), S137–S145 (2013).

    Article  PubMed  Google Scholar 

  40. DeKosky, S. T. & Scheff, S. W. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann. Neurol. 27, 457–464 (1990).

    Article  CAS  PubMed  Google Scholar 

  41. Blennow, K., Bogdanovic, N., Alafuzoff, I., Ekman, R. & Davidsson, P. Synaptic pathology in Alzheimer's disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the APOE4 allele. J. Neural Transm. 103, 603–618 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Giacobini, E. & Gold, G. Alzheimer disease therapy—moving from amyloid-β to tau. Nat. Rev. Neurol. 9, 677–686 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Thal, D. R., Griffin, W. S., de Vos, R. A. & Ghebremedhin, E. Cerebral amyloid angiopathy and its relationship to Alzheimer's disease. Acta Neuropathol. 115, 599–609 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Weller, R. O., Subash, M., Preston, S. D., Mazanti, I. & Carare, R. O. Perivascular drainage of amyloid-β peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol. 18, 253–266 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Mosconi, L. et al. Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis. Neurology 64, 1860–1867 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Ferris, S. H. et al. Positron emission tomography in the study of aging and senile dementia. Neurobiol. Aging 1, 127–131 (1981).

    Article  Google Scholar 

  47. de Leon, M. J. in Alzheimer: 100 Years and Beyond Illness 1st edn (eds Jucker, M. et al.) 385–390 (Springer, 2006).

    Book  Google Scholar 

  48. de Leon, M. J. et al. The radiologic prediction of Alzheimer disease: the atrophic hippocampal formation. AJNR Am. J. Neuroradiol. 14, 897–906 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Frisoni, G. B., Fox, N. C., Jack, C. R. Jr, Scheltens, P. & Thompson, P. M. The clinical use of structural MRI in Alzheimer disease. Nat. Rev. Neurol. 6, 67–77 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Cohen, A. D. & Klunk, W. E. Early detection of Alzheimer's disease using PiB and FDG PET. Neurobiol. Disease (2014).

  51. Blennow, K. CSF biomarkers for AD: state of the art and new developments. Neurobiol. Aging 35, S3–S3 (2014).

    Article  Google Scholar 

  52. Harada, R. et al. [18F]THK-5117 PET for assessing neurofibrillary pathology in Alzheimer's disease Eur. J. Nucl. Med. Mol. Imaging 42, 1052–1061 (2015).

    Article  CAS  PubMed  Google Scholar 

  53. Balasubramanian, A. B., Kawas, C. H., Peltz, C. B., Brookmeyer, R. & Corrada, M. M. Alzheimer disease pathology and longitudinal cognitive performance in the oldest-old with no dementia. Neurology 79, 915–921 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Blennow, K., Hampel, H., Weiner, M. & Zetterberg, H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat. Rev. Neurol. 6, 131–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Villemagne, V. L., Fodero-Tavoletti, M. T., Masters, C. L. & Rowe, C. C. Tau imaging: early progress and future directions. Lancet Neurol. 14, 114–124 (2015).

    Article  PubMed  Google Scholar 

  56. Kiffin, R., Bandyopadhyay, U. & Cuervo, A. M. Oxidative stress and autophagy. Antioxid. Redox Signal. 8, 152–162 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Yin, K.-J. et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-β peptide catabolism. J. Neurosci. 26, 10939–10948 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wilcock, D. M. et al. Microglial activation facilitates Aβ plaque removal following intracranial anti-Aβ antibody administration. Neurobiol. Dis. 15, 11–20 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Hawkes, C. A. & McLaurin, J. Selective targeting of perivascular macrophages for clearance of β-amyloid in cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 106, 1261–1266 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Guenette, S. Y. Astrocytes: a cellular player in Aβ clearance and degradation. Trends Mol. Med. 9, 279–280 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R. & Begley, D. J. Structure and function of the blood–brain barrier. Neurobiol. Dis. 37, 13–25 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Zlokovic, B. V., Begley, D. J. & Chain-Eliash, D. G. Blood–brain barrier permeability to leucine-enkephalin, D-alanine2-D-leucine5-enkephalin and their N-terminal amino acid (tyrosine). Brain Res. 336, 125–132 (1985).

    Article  CAS  PubMed  Google Scholar 

  63. Zlokovic´, B. V., Lipovac, M. N., Begley, D. J., Davson, H. & Rakic´, L. Transport of leucine-enkephalin across the blood–brain barrier in the perfused guinea pig brain. J. Neurochem. 49, 310–315 (1987).

    Article  PubMed  Google Scholar 

  64. Zlokovic, B. V. Cerebrovascular permeability to peptides: manipulations of transport systems at the blood-brain barrier. Pharm. Res. 12, 1395–1406 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Hermann, D. M. & ElAli, A. The abluminal endothelial membrane in neurovascular remodeling in health and disease. Sci. Signal. 5, re4 (2012).

    Article  PubMed  CAS  Google Scholar 

  66. Thrane, A. S., Thrane, V. R. & Nedergaard, M. Drowning stars: reassessing the role of astrocytes in brain edema. Trends Neurosci. 37, 620–628 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Syková, E. & Nicholson, C. Diffusion in brain extracellular space. Physiol. Rev. 88, 1277–1340 (2008).

    Article  PubMed  Google Scholar 

  68. Wong, A. D. et al. The blood–brain barrier: an engineering perspective. Front. Neuroeng. 6, 7 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Felgenhauer, K. Protein filtration and secretion at human body fluid barriers. Pflügers Arch. 384, 9–17 (1980).

    Article  CAS  PubMed  Google Scholar 

  70. Mathiisen, T. M., Lehre, K. P., Danbolt, N. C. & Ottersen, O. P. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58, 1094–1103 (2010).

    Article  PubMed  Google Scholar 

  71. Garai, K., Crick, S. L., Mustafi, S. M. & Frieden, C. Expression and purification of amyloid-β peptides from Escherichia coli. Protein Expr. Purif. 66, 107–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yang, L. et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 11, 107 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Abbott, N. J. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem. Int. 45, 545–552 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Milford, H. in Studies in Intracranial Physiology and Surgery 1st edn Ch. 1 (ed. Cushing, H.) 1–50 (Oxford University Press, 1926).

    Google Scholar 

  75. Loukas, M. et al. The lymphatic system: a historical perspective. Clin. Anat. 24, 807–816 (2011).

    Article  PubMed  Google Scholar 

  76. Fenstermacher, J. & Patlak, C. in Fluid Environment of the Brain 1st edn Ch. 12 (ed. Cserr, H.) 201–214 (Academic Press, 1975).

    Book  Google Scholar 

  77. Cserr, H. F. Physiology of the choroid plexus. Physiol. Rev. 51, 273–311 (1971).

    Article  CAS  PubMed  Google Scholar 

  78. Cserr, H., Cooper, D., Suri, P. & Patlak, C. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am. J. Physiol. 240, F319–F328 (1981).

    CAS  PubMed  Google Scholar 

  79. Rennels, M. L., Gregory, T. F., Blaumanis, O. R., Fujimoto, K. & Grady, P. A. Evidence for a 'paravascular' fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res. 326, 47–63 (1985).

    Article  CAS  PubMed  Google Scholar 

  80. Pullen, R. G., DePasquale, M. & Cserr, H. F. Bulk flow of cerebrospinal fluid into brain in response to acute hyperosmolality. Am. J. Physiol. 253, F538–F545 (1987).

    CAS  PubMed  Google Scholar 

  81. Szentistvanyi, I., Patlak, C. S., Ellis, R. A. & Cserr, H. F. Drainage of interstitial fluid from different regions of rat brain. Am. J. Physiol. 246, F835–F844 (1984).

    CAS  PubMed  Google Scholar 

  82. Carare, R. et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol. Appl. Neurobiol. 34, 131–144 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Preston, S., Steart, P., Wilkinson, A., Nicoll, J. & Weller, R. Capillary and arterial cerebral amyloid angiopathy in Alzheimer's disease: defining the perivascular route for the elimination of amyloid β from the human brain. Neuropathol. Appl. Neurobiol. 29, 106–117 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Hawkes, C. A., Jayakody, N., Johnston, D. A., Bechmann, I. & Carare, R. O. Failure of perivascular drainage of β-amyloid in cerebral amyloid angiopathy. Brain Pathol. 24, 396–403 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Iliff, J. J. et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J. Clin. Invest. 123, 1299–1309 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hladky, S. B. & Barrand, M. A. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11, 26 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Jessen, N. A., Munk, A. S. F., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner's guide. Neurochem. Res. http://dx.doi.org/10.1007/s11064-015-1581-6.

  88. Arbel-Ornath, M. et al. Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models. Acta Neuropathol. 126, 353–364 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Nimmerjahn, A. Two-photon imaging of microglia in the mouse cortex in vivo. Cold Spring Harb. Protoc. http://dx.doi.org/10.1101/pdb.prot069294.

  90. Navari, R., Wei, E., Kontos, H. & Patterson, J. Comparison of the open skull and cranial window preparations in the study of the cerebral microcirculation. Microvasc. Res. 16, 304–315 (1978).

    Article  CAS  PubMed  Google Scholar 

  91. Bacskai, B. J. et al. Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat. Med. 7, 369–372 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Kawamura, S. et al. An improved closed cranial window technique for investigation of blood–brain barrier function and cerebral vasomotor control in the rat. Int. J. Microcirc. Clin. Exp. 9, 369–383 (1990).

    CAS  PubMed  Google Scholar 

  93. Igarashi, H., Tsujita, M., Kwee, I. L. & Nakada, T. Water influx into cerebrospinal fluid is primarily controlled by aquaporin-4, not by aquaporin-1: 17O JJVCPE MRI study in knockout mice. Neuroreport 25, 39–43 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Oreškovic´, D. & Klarica, M. The formation of cerebrospinal fluid: nearly a hundred years of interpretations and misinterpretations. Brain Res. Rev. 64, 241–262 (2010).

    Article  PubMed  Google Scholar 

  95. Bering E. A. Jr. Water exchange of central nervous system and cerebrospinal fluid. J. Neurosurgery 9, 275–287 (1952).

    Article  Google Scholar 

  96. Johanson, C. E. et al. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res. 5, 10 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Wraith, D. C. & Nicholson, L. B. The adaptive immune system in diseases of the central nervous system. J. Clin. Invest. 122, 1172–1179 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Pollay, M. The function and structure of the cerebrospinal fluid outflow system. Cerebrospinal Fluid Res. 7, 9 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Bradbury, M., Cserr, H. & Westrop, R. Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am. J. Physiol. 240, F329–F336 (1981).

    CAS  PubMed  Google Scholar 

  100. Bradbury, M. & Westrop, R. Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit. J. Physiol. 339, 519–534 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bero, A. W. et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat. Neurosci. 14, 750–756 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Neve, R. L. & McPhie, D. L. Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis. Biochim. Biophys. Acta 1772, 430–437 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Chow, V. W., Mattson, M. P., Wong, P. C. & Gleichmann, M. An overview of APP processing enzymes and products. Neuromol. Med. 12, 1–12 (2010).

    Article  CAS  Google Scholar 

  104. Blennow, K., de Leon, M. J. & Zetterberg, H. Alzheimer's disease. Lancet 368, 387–403 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Zheng, L. et al. Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system. Transl. Neurodegener. 1, 19 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Morris, A. W., Carare, R. O., Schreiber, S. & Hawkes, C. A. The cerebrovascular basement membrane: role in the clearance of β-amyloid and cerebral amyloid angiopathy. Front. Aging Neurosci. 6, 251 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Mueller-Steiner, S. et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron 51, 703–714 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Moro, M. L. et al. APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38. Acta Neuropathol. 124, 809–821 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Glabe, C. Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease. J. Mol. Neurosci. 17, 137–145 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Dawkins, E. & Small, D. H. Insights into the physiological function of the beta-amyloid precursor protein: beyond Alzheimer's disease. J. Neurochem. 129, 756–769 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jarrett, J. T., Berger, E. P. & Lansbury, P. T. Jr. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693–4697 (1993).

    Article  CAS  PubMed  Google Scholar 

  112. Braak, H., Zetterberg, H., Del Tredici, K. & Blennow, K. Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-β changes occur before increases of tau in cerebrospinal fluid. Acta Neuropathol. 126, 631–641 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Grimm, M. O. et al. Neprilysin and Aβ clearance: impact of the APP intracellular domain in NEP regulation and implications in Alzheimer's disease. Front. Aging Neurosci. 5, 98 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Lührs, T. et al. 3D structure of Alzheimer's amyloid-β(1–42) fibrils. Proc. Natl. Acad. Sci. USA 102, 17342–17347 (2005).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  115. Schnabel, J. Amyloid: little proteins, big clues. Nature 475, S12–S14 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Perez, F. P. et al. Late-onset Alzheimer's disease, heating up and foxed by several proteins: pathomolecular effects of the aging process. J. Alzheimers Dis. 40, 1–17 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang, L., Sheng, R. & Qin, Z. The lysosome and neurodegenerative diseases. Acta Biochim. Biophys. Sin. (Shanghai) 41, 437–445 (2009).

    Article  CAS  Google Scholar 

  118. Querfurth, H. W. & LaFerla, F. M. Mechanisms of disease. N. Engl. J. Med. 362, 329–344 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Iwata, N. et al. Metabolic regulation of brain Aβ by neprilysin. Science 292, 1550–1552 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Miners, J. S. et al. Aβ-degrading enzymes in Alzheimer's disease. Brain Pathol. 18, 240–252 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nalivaeva, N. N., Beckett, C., Belyaev, N. D. & Turner, A. J. Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer's disease? J. Neurochem. 120, 167–185 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Eckman, E. A., Reed, D. K. & Eckman, C. B. Degradation of the Alzheimer's amyloid β peptide by endothelin-converting enzyme. J. Biol. Chem. 276, 24540–24548 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Qiu, W. Q. et al. Insulin-degrading enzyme regulates extracellular levels of amyloid β-protein by degradation. J. Biol. Chem. 273, 32730–32738 (1998).

    Article  CAS  PubMed  Google Scholar 

  125. Yoon, S. S. & Jo, S. A. Mechanisms of amyloid-β peptide clearance: potential therapeutic targets for Alzheimer's disease. Biomol. Ther. (Seoul) 20, 245–255 (2012).

    Article  CAS  Google Scholar 

  126. Wang, D.-S., Iwata, N., Hama, E., Saido, T. C. & Dickson, D. W. Oxidized neprilysin in aging and Alzheimer's disease brains. Biochem. Biophys. Res. Commun. 310, 236–241 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Yasojima, K., McGeer, E. & McGeer, P. Relationship between beta amyloid peptide generating molecules and neprilysin in Alzheimer disease and normal brain. Brain Res. 919, 115–121 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Lim, N. K. et al. Investigation of matrix metalloproteinases, MMP-2 and MMP-9, in plasma reveals a decrease of MMP-2 in Alzheimer's disease. J. Alzheimers Dis. 26, 779–786 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Morrone, C. D., Liu, M., Black, S. E. & McLaurin, J. Interaction between therapeutic interventions for Alzheimer's disease and physiological Aβ clearance mechanisms. Front. Aging Neurosci. 7 (2015).

  130. Lucin, K. M. & Wyss-Coray, T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64, 110–122 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Cho, M. H. et al. Autophagy in microglia degrades extracellular beta-amyloid fibrils and regulates the NLRP3 inflammasome. Autophagy 10, 1761–1775 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Nagele, R. G., D'Andrea, M. R., Lee, H., Venkataraman, V. & Wang, H.-Y. Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 971, 197–209 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. Lee, C. D. & Landreth, G. E. The role of microglia in amyloid clearance from the AD brain. J. Neural Transm. 117, 949–960 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Nixon, R. A. & Cataldo, A. M. Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease. J. Alzheimers Dis. 9, 277–289 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. Chesser, A. S., Pritchard, S. M. & Johnson, G. V. Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease. Front. Neurol. 4, 122 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Pascale, C. L. et al. Amyloid-beta transporter expression at the blood–CSF barrier is age-dependent. Fluids Barriers CNS 8, 21 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ito, S., Ohtsuki, S. & Terasaki, T. Functional characterization of the brain-to-blood efflux clearance of human amyloid-β peptide (1–40) across the rat blood–brain barrier. Neurosci. Res. 56, 246–252 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Ito, S., Ohtsuki, S., Kamiie, J., Nezu, Y. & Terasaki, T. Cerebral clearance of human amyloid-β peptide (1–40) across the blood–brain barrier is reduced by self-aggregation and formation of low-density lipoprotein receptor-related protein-1 ligand complexes. J. Neurochem. 103, 2482–2490 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Ito, S., Ueno, T., Ohtsuki, S. & Terasaki, T. Lack of brain-to-blood efflux transport activity of low-density lipoprotein receptor-related protein-1 (LRP-1) for amyloid-β peptide(1–40) in mouse: involvement of an LRP-1-independent pathway. J. Neurochem. 113, 1356–1363 (2010).

    CAS  PubMed  Google Scholar 

  140. Panzenboeck, U. et al. ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood–brain barrier constituted of porcine brain capillary endothelial cells. J. Biol. Chem. 277, 42781–42789 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Akanuma, S. et al. ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-β peptide (1–40) at the blood–brain barrier. Neurochem. Int. 52, 956–961 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Fitz, N. F. et al. Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J. Neurosci. 32, 13125–13136 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. ElAli, A. & Rivest, S. The role of ABCB1 and ABCA1 in beta-amyloid clearance at the neurovascular unit in Alzheimer's disease. Front. Physiol. 4, 45 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Ito, S. et al. Involvement of insulin-degrading enzyme in insulin- and atrial natriuretic peptide-sensitive internalization of amyloid-beta peptide in mouse brain capillary endothelial cells. J. Alzheimers Dis. 38, 185–200 (2014).

    Article  CAS  PubMed  Google Scholar 

  145. Deane, R. et al. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J. Clin. Invest. 122, 1377 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zlokovic, B. V., Deane, R., Sagare, A. P., Bell, R. D. & Winkler, E. A. Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer's amyloid beta-peptide elimination from the brain. J. Neurochem. 115, 1077–1089 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Pahnke, J., Langer, O. & Krohn, M. Alzheimer's and ABC transporters—new opportunities for diagnostics and treatment. Neurobiol. Dis. 72, A54–A60. (2014).

    Article  CAS  Google Scholar 

  148. Cai, Z. Y., Yan, L. J. & Ratka, A. Telomere shortening and Alzheimer's disease. Neuromol. Med. 15, 25–48 (2013).

    Article  CAS  Google Scholar 

  149. Krstic, D. & Knuesel, I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 9, 25–34 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Kanekiyo, T., Xu, H. & Bu, G. ApoE and Aβ in Alzheimer's disease: accidental encounters or partners? Neuron 81, 740–754 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Verghese, P. B. et al. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc. Natl Acad. Sci. USA 110, E1807–E1816 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Liu, C.-C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wildsmith, K. R., Holley, M., Savage, J. C., Skerrett, R. & Landreth, G. E. Evidence for impaired amyloid beta clearance in Alzheimer's disease. Alzheimers Res. Ther. 5, 33 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Miyata, M. & Smith, J. D. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloid peptides. Nat. Genet. 14, 55–61 (1996).

    Article  CAS  PubMed  Google Scholar 

  155. Smith, M. A., Rottkamp, C. A., Nunomura, A., Raina, A. K. & Perry, G. Oxidative stress in Alzheimer's disease. Biochim. Biophys. Acta 1502, 139–144 (2000).

    Article  CAS  PubMed  Google Scholar 

  156. Bell, R. D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Li, M., Chen, L., Lee, D. H., Yu, L.-C. & Zhang, Y. The role of intracellular amyloid β in Alzheimer's disease. Prog. Neurobiol. 83, 131–139 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Winkler, E. A., Bell, R. D. & Zlokovic, B. V. Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398–1405 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Sagare, A. P., Bell, R. D. & Zlokovic, B. V. Neurovascular defects and faulty amyloid-β vascular clearance in Alzheimer's disease. J. Alzheimers Dis. 33, S87–S100 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Weller, R. O. et al. Cerebral amyloid angiopathy: amyloid β accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am. J. Pathol. 153, 725–733 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hawkes, C. A. et al. Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele. PLoS ONE 7, e41636 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Carare, R. O. et al. Immune complex formation impairs the elimination of solutes from the brain: implications for immunotherapy in Alzheimer's disease. Acta Neuropathol. Commun. 1, 48 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Hawkes, C. A. et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 121, 431–443 (2011).

    Article  PubMed  Google Scholar 

  164. Weller, R. O., Hawkes, C. A., Carare, R. O. & Hardy, J. Does the difference between PART and Alzheimer's disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau? Acta Neuropathol. 129, 763–766 (2015).

    Article  PubMed  Google Scholar 

  165. Pezzini, A. & Padovani, A. Cerebral amyloid angiopathy-related hemorrhages. Neurol. Sci. 29, 260–263 (2008).

    Article  Google Scholar 

  166. Sakai, K. et al. Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy. Acta Neuropathol. 128, 777–789 (2014).

    Article  CAS  PubMed  Google Scholar 

  167. Schley, D., Carare-Nnadi, R., Please, C., Perry, V. & Weller, R. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J. Theor. Biol. 238, 962–974 (2006).

    Article  CAS  PubMed  Google Scholar 

  168. Hawkes, C. A. et al. Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Aging Cell 12, 224–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Hawkes, C. A., Gentleman, S. M., Nicoll, J. A. & Carare, R. O. Prenatal high-fat diet alters the cerebrovasculature and clearance of β-amyloid in adult offspring. J. Pathol. 235, 619–631 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Manousopoulou, A. et al. Are you also what your mother eats? Distinct proteomic portrait as a result of maternal high-fat diet in the cerebral cortex of the adult mouse. Int. J. Obes. (Lond.) (2015).

  171. Iliff, J. J. & Nedergaard, M. Is there a cerebral lymphatic system? Stroke 44, S93–S95 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Stoodley, M. A., Brown, S. A., Brown, C. J. & Jones, N. R. Arterial pulsation-dependent perivascular cerebrospinal fluid flow into the central canal in the sheep spinal cord. J. Neurosurg. 86, 686–693 (1997).

    Article  CAS  PubMed  Google Scholar 

  173. Iliff, J. J. et al. Cerebral arterial pulsation drives paravascular CSF–interstitial fluid exchange in the murine brain. J. Neurosci. 33, 18190–18199 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Maurizi, C. Recirculation of cerebrospinal fluid through the tela choroidae is why high levels of melatonin can be found in the lateral ventricles. Med. Hypotheses 35, 154–158 (1991).

    Article  CAS  PubMed  Google Scholar 

  175. Nedergaard, M. Garbage truck of the brain. Science 340, 1529–1530 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hartl, F. U. & Hayer-Hartl, M. Converging concepts of protein folding in vitro and in vivo. Nat. Struct. Mol. Biol. 16, 574–581 (2009).

    Article  CAS  PubMed  Google Scholar 

  177. Yang, W. et al. Aquaporin-4 mediates astrocyte response to β-amyloid. Mol. Cell. Neurosci. 49, 406–414 (2012).

    Article  CAS  PubMed  Google Scholar 

  178. Ren, Z. et al. 'Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. J. Cereb. Blood Flow Metab. 33, 834–845 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).

    Article  CAS  PubMed  Google Scholar 

  180. McKinley, J., McCarthy, A. & Lynch, T. Don't lose sleep over neurodegeneration-it helps clear amyloid beta. Front. Neurol. 4, 206 (2013).

    PubMed  PubMed Central  Google Scholar 

  181. Mendelsohn, A. R. & Larrick, J. W. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases. Rejuvenation Res. 16, 518–523 (2013).

    Article  CAS  PubMed  Google Scholar 

  182. O'Donnell, J., Ding, F. & Nedergaard, M. Distinct functional states of astrocytes during sleep and wakefulness: is norepinephrine the master regulator? Curr. Sleep Med. Rep. 1, 1–8 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Wu, Y.-H. & Swaab, D. F. Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer's disease. Sleep Med. 8, 623–636 (2007).

    Article  PubMed  Google Scholar 

  184. Ju, Y.-E. et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 70, 587–593 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Musiek, E. S. Circadian clock disruption in neurodegenerative diseases: cause and effect? Front. Pharmacol. 6, 29 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Deane, R. et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron 43, 333–344 (2004).

    Article  CAS  PubMed  Google Scholar 

  187. Lin, T.-W. et al. Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer's disease (APP/PS1) transgenic mice. Neurobiol. Learn. Mem. 118, 189–197 (2015).

    Article  CAS  PubMed  Google Scholar 

  188. Herring, A. et al. Environmental enrichment counteracts Alzheimer's neurovascular dysfunction in TgCRND8 mice. Brain Pathol. 18, 32–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  189. Richter, H. et al. Wheel-running in a transgenic mouse model of Alzheimer's disease: protection or symptom? Behav. Brain Res. 190, 74–84 (2008).

    Article  CAS  PubMed  Google Scholar 

  190. Marques, F., Sousa, J. C., Sousa, N. & Palha, J. A. Blood–brain-barriers in aging and in Alzheimer's. Mol. Neurodegener. 8, 38 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Picken, M. M. The changing concepts of amyloid. Arch. Pathol. Lab. Med. 125, 38–43 (2001).

    CAS  PubMed  Google Scholar 

  192. Nakada, T., Igarashi, H., Suzuki, Y. & Kwee, I. Alzheimer patients show significant disturbance in water influx into CSF space strongly supporting β-amyloid clearance hypothesis [abstract S58.0001]. Neurology 82 (Suppl. 1) S58.001 (2014).

    Google Scholar 

  193. Serot, J. M., Zmudka, J. & Jouanny, P. A possible role for CSF turnover and choroid plexus in the pathogenesis of late onset Alzheimer's disease. J. Alzheimers Dis. 30, 17–26 (2012).

    Article  CAS  PubMed  Google Scholar 

  194. Erickson, M. A. & Banks, W. A. Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease. J. Cereb. Blood Flow Metab. 33, 1500–1513 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Fujiyoshi, M. et al. Amyloid-β peptide(1–40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood–cerebrospinal fluid barrier. J. Neurochem. 118, 407–415 (2011).

    Article  CAS  PubMed  Google Scholar 

  196. Silverberg, G. D., Mayo, M., Saul, T., Rubenstein, E. & McGuire, D. Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol. 2, 506–511 (2003).

    Article  PubMed  Google Scholar 

  197. Silverberg, G., Mayo, M., Saul, T., Fellmann, J. & McGuire, D. Elevated cerebrospinal fluid pressure in patients with Alzheimer's. Cerebrospinal Fluid Res. 3, 7 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Pappolla, M. et al. Evidence for lymphatic Aβ clearance in Alzheimer's transgenic mice. Neurobiol. Dis. 71, 215–219 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Shea, T. & Beermann, M. Respective roles of neurofilaments, microtubules, MAP1B, and tau in neurite outgrowth and stabilization. Mol. Biol. Cell 5, 863–875 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Binder, L. I., Guillozet-Bongaarts, A. L., Garcia-Sierra, F. & Berry, R. W. Tau, tangles, and Alzheimer's disease. Biochim. Biophys. Acta 1739, 216–223 (2005).

    Article  CAS  PubMed  Google Scholar 

  201. Yamada, K. et al. Neuronal activity regulates extracellular tau in vivo. J. Exp. Med. 211, 387–393 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Avila, J., Simon, D., Diaz-Hernandez, M., Pintor, J. & Hernandez, F. Sources of extracellular tau and its signaling. J. Alzheimers Dis. 40, (Suppl. 1) S7–S15 (2014).

    Article  PubMed  CAS  Google Scholar 

  203. Irazuzta, J. E., de Courten-Myers, G., Zemlan, F. P., Bekkedal, M. Y. & Rossi, J. 3rd. Serum cleaved tau protein and neurobehavioral battery of tests as markers of brain injury in experimental bacterial meningitis. Brain Res. 913, 95–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  204. Castillo-Carranza, D. L. et al. Passive immunization with tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J. Neurosci. 34, 4260–4272 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Litersky, J. M. & Johnson, G. Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. J. Biol. Chem. 267, 1563–1568 (1992).

    CAS  PubMed  Google Scholar 

  206. Medina, M. & Avila, J. The role of extracellular tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci. 8, 13 (2014).

    Google Scholar 

  207. Gómez-Ramos, A. et al. Characteristics and consequences of muscarinic receptor activation by tau protein. Europ. Neuropsychopharmacol. 19, 708–717 (2009).

    Article  CAS  Google Scholar 

  208. David, D. C. et al. Proteasomal degradation of tau protein. J. Neurochemist. 83, 176–185 (2002).

    Article  CAS  Google Scholar 

  209. Cirrito, J. R. et al. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-β metabolism and half-life. J. Neurosci. 23, 8844–8853 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Iliff, J. J. et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J. Neurosci. 34, 16180–16193 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Plog, B. A. et al. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J. Neurosci. 35, 518–526 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Bateman, R. J. et al. Quantifying CNS protein production and clearance rates in humans using in vivo stable isotope labeling, immunoprecipitation, and tandem mass spectrometry. Nat. Med. 12, 856 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Authors and Affiliations

  1. New York University School of Medicine, 660 First Avenue, New York, 10016, NY, 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, 10016, NY, 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, 90089, CA, 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, Paris, 75006, 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.

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Correspondence to Mony J. de Leon.

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

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Tarasoff-Conway, J., Carare, R., Osorio, R. et al. Clearance systems in the brain—implications for Alzheimer disease. Nat Rev Neurol 11, 457–470 (2015). https://doi.org/10.1038/nrneurol.2015.119

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