Clearance systems in the brain—implications for Alzheimer disease

Tarasoff-Conway, Jenna M.; Carare, Roxana O.; Osorio, Ricardo S.; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V.; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J.

doi:10.1038/nrneurol.2015.119

Cited by 1,678Alzheimer's disease research and treatmentsCerebrospinal fluid and hydrocephalusNeuroinflammation and Neurodegeneration Mechanisms

Clearance systems in the brain—implications for Alzheimer disease

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Tarasoff-Conway, Jenna M., Carare, Roxana O., Osorio, Ricardo S., Glodzik, Lidia, Butler, Tracy, Fieremans, Els, Axel, Leon, Rusinek, Henry +8 more·2015·Nature Reviews Neurology

DOI 10.1038/nrneurol.2015.119PMC PMC4694579

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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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Concomitant BBB dysfunction reduces intracerebral transport of glucose and other nutrients and decreases removal of excess metabolites, thus altering homeostasis in the central nervous system.
“The concomitant BBB dysfunction not only reduces the intracerebral transport of glucose and other nutrients,[ 10 ] but also decreases the removal of excess metabolites,[ 11 ] thus alters the homeostasis in the central nervous system (CNS).”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [11]
The “Factors impairing amyloid-β clearance in AD” subsection (page unavailable) says that BBB clearance of amyloid-β is impaired in AD, including through reduced expression of efflux transporters. This supports decreased removal of a specific brain protein, but does not establish reduced removal of excess metabolites generally. The glucose-and-nutrient clause is attributed to citation [10], not this source. (LLM, conf=0.83)
Experimental — accuracy not yet measured
RAP specifically binds to RAGE overexpressing on the endothelium of Alzheimer's disease cerebral vasculature, causing RAP-RL accumulation along the cerebral microvasculature.
“The major reason for the accumulation of RAP‐RL along the cerebral microvasculature lies in that a key component of the nanostructure, RAP, a peptide derived from RAGE's nature ligand S100P, can specifically bind to RAGE overexpressing on the endothelium of AD cerebral vasculature.[ 15 , 38 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [15]
The 'Factors impairing amyloid-β clearance in AD' passage under Blood-brain barrier clearance states that RAGE expression is upregulated in AD. It does not address RAP, its derivation from S100P, specific RAP–RAGE binding, or RAP-RL accumulation along cerebral microvasculature. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Expression of AQP4 on astrocytic endfeet decreases and their perivascular polarization is inhibited in Alzheimer's disease, ultimately leading to lymphatic clearance dysfunction.
“Moreover, the expression of AQP4 on astrocytic endfeet decrease and their perivascular polarization is inhibited, ultimately leading to lymphatic clearance dysfunction.[ 11 , 43 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [11]
In “Clearance of amyloid-β > Interstitial fluid bulk-flow clearance” (page unavailable), the paper says AQP4 expression could decrease in AD and that AQP4-dependent glymphatic clearance is important for Aβ removal. It reports mislocalization of AQP4 away from perivascular endfeet in traumatic brain injury, not as an established finding in AD. It also does not establish that these changes ultimately cause lymphatic clearance dysfunction in AD. (LLM, conf=0.88)
Experimental — accuracy not yet measured
An important clearance pathway for cerebral Aβ is steady transport across the blood-brain barrier.
“An important clearance pathway for cerebral Aβ is the steady transport across the blood–brain barrier (BBB) [11].”
From PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier (2022) · cites this paper as [11]
RAP, a peptide derived from RAGE's natural ligand S100B, can bind RAGE effectively.
“RAP, a peptide derived from RAGE's nature ligand, S100B, can bind RAGE effectively.[ 15 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [15]
The Blood-brain barrier clearance section discusses RAGE-mediated transport of amyloid-β, but does not address RAP or S100B. Searches for a RAP peptide derived from S100B and for S100B as a RAGE ligand found no passage about the claimed peptide binding. (LLM, conf=0.76)
Experimental — accuracy not yet measured

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[47]de Leon MJ Jucker M Alzheimer: 100 Years and Beyond Illness 2006 1st edn Springer 385 390
[74]Milford H Cushing H Studies in Intracranial Physiology and Surgery 1926 1st edn Oxford University Press 1 50 Ch. 1
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Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways
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Authors: Tarasoff-Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., Fieremans, E., Axel, L., Rusinek, H., Nicholson, C., Zlokovic, B. V., Frangione, B., Blennow, K., Ménard, J., Zetterberg, H., Wisniewski, T., & de Leon, M. J.
Affiliations: New York University (US)
Southampton General Hospital (GB)
NYU Langone Health (US)
University of Gothenburg (SE)
Université Paris Descartes (FR)
ORCID: Carare, Roxana O.
Osorio, Ricardo S.
Glodzik, Lidia
Butler, Tracy
Fieremans, Els
Axel, Leon
Rusinek, Henry
Nicholson, Charles
Blennow, Kaj
Ménard, Joël
Zetterberg, Henrik
Venue: Nature Reviews Neurology
Publisher: Springer Science and Business Media LLC
Published: 2015-07-21
Volume: 11
Issue: 8
Pages: 457-470
ISSN: 1759-4758 (ISSN-L)
1759-4766
DOI: 10.1038/nrneurol.2015.119
PMC: PMC4694579
OpenAlex: W1767010801
Cited by: 1,678
References: 216
Citations by year: 2026: 165 · 2025: 178 · 2024: 190 · 2023: 163 · 2022: 184 · 2021: 183 · 2020: 162 · 2019: 137 · 2018: 118 · 2017: 129 · 2016: 53 · 2015: 15
FWCI: 12.83
Type: journal article
Language: en
Update notices: erratum (2016-03-29)
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Neurology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: National Institute on Aging (AG008051, AG022374, R01AG022374, AG20245, AG 12101, R01AG012101, P30AG008051, R01AG020245, R01AG013616, AG 13616)
National Heart, Lung, and Blood Institute (HL118624, R01HL118624, HL111724, R01HL111724)
National Institute of Neurological Disorders and Stroke (NS028642, R01NS028642)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, amyloid-beta clearance, glymphatic system, meningeal lymphatic vessels, blood-brain barrier, astrocytes, tau hyperphosphorylation, amyloid plaques, brain waste clearance
MeSH terms: Alzheimer Disease, Blood-Brain Barrier, Brain, Cerebrospinal Fluid Proteins, Humans, Lymphatic System, Risk Factors, Biomarkers, Amyloid beta-Peptides, tau Proteins, Extracellular Fluid, Proteolysis, Absorption, Physiological

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