The DOI matches its Crossref record; 216 of the 216 references it cites were found in a registry or an index.
Clearance systems in the brain—implications for Alzheimer disease
Open accessAbstract
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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“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Due to the lack of appropriate model systems, the role of LRP1 at the BBB and the overall relevance of BBB clearance are insufficiently understood and debated (4,7).”
From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Glial cells such as astrocytes and microglia also play a role in Aβ42 clearance by several mechanisms including proteolytic degradation of endocytosed proteins, clearance through the blood brain barrier, and clearance from to the CSF via the glymphatic pathway [46].”
From The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates (2020) · cites this paper as [46]
Experimental — accuracy not yet measured
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In the citing paper
“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]
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“Low Aβ levels within the healthy brain are maintained through degradation, elimination via interstitial fluid (ISF) bulk flow, cerebrospinal fluid (CSF) absorption into the circulatory and lymphatic system, or transport across the blood-brain barrier (BBB) (3,4).”
From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [4]
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In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“AQP4 levels are reduced in CAA; since AQP4 plays a vital role in glymphatic Aβ clearance in AD brain parenchyma, this consequently impairs Aβ clearance [606, 608].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [606]
In the citing paper
“AQP4 levels are reduced in CAA; since AQP4 plays a vital role in glymphatic Aβ clearance in AD brain parenchyma, this consequently impairs Aβ clearance [606, 608].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [606]
In the citing paper
“It has been suggested that vascular damage associated with CAA disrupts vascular drainage and homeostasis in the CNS, thereby impairing Aβ clearance and aggravating AD pathogenesis [606].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [606]
In the citing paper
“In contrast, Aβ peptides in the CNS can also move into the circulatory system, where the peptides are phagocytosed by the monocytes or neutrophils, directly degraded by the enzymes, or further transported to the peripheral organs or tissues for degradation or excretion.”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [28]
In the citing paper
“In a healthy brain, Ab homeostasis is maintained by a balance between its production and clearance, whereas in AD brain overproduction and/or reduced clearance of Ab result in the formation of amyloid deposits (4).”
From Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia (2017) · cites this paper as [4]
In the citing paper
“We and others have shown that both neurons and glia can clear extracellular Ab through endocytosis for subsequent lysosomal degradation or secretion of amyloiddegrading enzymes for extracellular clearance (4,7).”
From Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia (2017) · cites this paper as [4]
In the citing paper
“Impairment of Ab uptake and clearance by neurons, glia, and blood-brain-barrier endothelial cells may explain why the level of Ab is elevated and accumulates during AD progression (4).”
From Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia (2017) · cites this paper as [4]
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Citations
Cites
Items 201–216 of 216
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Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?
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Metadata
- 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
- Venue
- Nature Reviews Neurology
- Published
- 2015-07-21
- Volume
- 11
- Issue
- 8
- Pages
- 457-470
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- 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
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › 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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