Transport Pathways for Clearance of Human Alzheimer's Amyloid β-Peptide and Apolipoproteins E and J in the Mouse Central Nervous System
Open accessAbstract
Amyloid beta-peptide (Abeta) clearance from the central nervous system (CNS) maintains its low levels in brain. In Alzheimer's disease, Abeta accumulates in brain possibly because of its faulty CNS clearance and a deficient efflux across the blood-brain barrier (BBB). By using human-specific enzyme-linked immunosorbent assays, we measured a rapid 30 mins efflux at the BBB and transport via the interstitial fluid (ISF) bulk flow of human-unlabeled Abeta and of Abeta transport proteins, apolipoprotein E (apoE) and apoJ in mice. We show (i) Abeta40 is cleared rapidly across the BBB via low-density lipoprotein receptor-related protein (LRP)1 at a rate of 0.21 pmol/min g ISF or 6-fold faster than via the ISF flow; (ii) Abeta42 is removed across the BBB at a rate 1.9-fold slower compared with Abeta40; (iii) apoE, lipid-poor isoform 3, is cleared slowly via the ISF flow and across the BBB (0.03-0.04 pmol/min g ISF), and after lipidation its transport at the BBB becomes barely detectable within 30 mins; (iv) apoJ is eliminated rapidly across the BBB (0.16 pmol/min g ISF) via LRP2. Clearance rates of unlabeled and corresponding 125I-labeled Abeta and apolipoproteins were almost identical, but could not be measured at low physiologic levels by mass spectrometry. Amyloid beta-peptide 40 binding to apoE3 reduced its efflux rate at the BBB by 5.7-fold, whereas Abeta42 binding to apoJ enhanced Abeta42 BBB clearance rate by 83%. Thus, Abeta, apoE, and apoJ are cleared from brain by different transport pathways, and apoE and apoJ may critically modify Abeta clearance at the BBB.
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Under physiological conditions, perivascular interstitial fluid flow contributes to 15-20% of Aβ clearance from the mouse brain.
“For example, transport studies using radiolabeled and unlabeled Alzheimer's A 𝛃 peptide have shown that under physiological conditions, the perivascular ISF flow contributes to 15-20% of A 𝛃 clearance from the mouse brain (58, 535, 659), whereas 8085% is removed by transvascular BBB transport.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [58]
Results Tables 1 and 2 measure Aβ clearance via ISF flow in mice, supporting the claimed pathway's contribution. Their rates imply approximately 12–14% of clearance for Aβ40 and 22% for Aβ42, rather than a uniform 15–20%; the paper also does not specifically identify the measured flow as perivascular. Page numbers are unavailable in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAPOE4 compared with APOE3 and APOE2 diminishes Aβ clearance across the BBB.
“Studies in animal models support that APOE4 compared with APOE3 and APOE2 diminishes A 𝛃 clearance across the BBB (58, 135), which has been confirmed in transgenic APOE4 mice (98).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [58]
The Discussion reports that binding Aβ40 to apoE3 reduced its efflux across the BBB by 5.7-fold. But the study focused on apoE3 and says isoform-specific effects remain to be determined; it does not establish that APOE4 diminishes clearance compared with APOE3 or APOE2. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn animal models, APOE4 compared with APOE3 and APOE2 leads to impaired clearance of Aβ across the BBB and early BBB breakdown and transporters' dysregulation.
“and in animal models, APOE4 compared with APOE3 and APOE2 leads to impaired clearance of A 𝛃 across the BBB (58, 98, 135) and an early BBB breakdown and transporters' dysregulation (9, 60, 85, 437).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [58]
The Abstract and Discussion (pages unavailable) report that binding Aβ40 to apoE3 reduced its efflux across the BBB in mice. The Discussion explicitly says the study focused on apoE3 and that isoform-specific clearance differences remain to be determined; it does not establish that APOE4 impairs clearance more than APOE3 or APOE2. The separate BBB-breakdown and transporter-dysregulation clause carries different citations. (LLM, conf=0.84)
Experimental — accuracy not yet measuredApoE regulates both extracellular and intracellular Aβ clearance in the brain.
“Furthermore, recent studies strongly suggest that apoE regulates both extracellular and intracellular Aβ clearance in the brain (Bell et al., 2007; Deane et al., 2008; DeMattos et al., 2004; Jiang et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Bell et al., 2007
The Results and Discussion (page unavailable) show that binding to apoE3 slows Aβ40 clearance from brain interstitial fluid across the blood–brain barrier in mice. This supports an effect on extracellular clearance, but the paper does not establish that apoE regulates intracellular Aβ clearance. (LLM, conf=0.90)
Experimental — accuracy not yet measuredLRP1 binds Alzheimer's Aβ toxin and mediates its brain-to-blood clearance.
“LRP1 binds Alzheimer's A 𝛃 toxin and mediates its brain-to-blood clearance (58, 137, 535, 561).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [58]
APOJ or clusterin (CLU) binds to LRP2 (or megalin) at the blood-brain barrier, which mediates Aβ42 transport from brain to blood.
“Additionally, APOJ or clusterin (CLU) binds to LRP2 (or megalin) at the BBB, which mediates A 𝛃 42 transport from brain to blood (58, 700).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [58]
Under physiological conditions, 80-85% of Aβ is removed from the mouse brain by transvascular blood-brain barrier transport.
“whereas 8085% is removed by transvascular BBB transport.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [58]
LRP2 also known as glycoprotein 330 or megalin mediates transport of Aβ-clusterin complexes across the BBB.
“LRP2 also known as glycoprotein 330 (gp330) or megalin mediates transport of A 𝛃 -clusterin complexes across the BBB (58, 700).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [58]
ApoE regulates Aβ clearance in the brain.
“Furthermore, apoE has been shown to regulate Aβ clearance in the brain (Bell et al., 2007; Deane et al., 2008; DeMattos et al., 2004; Jiang et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Bell et al., 2007
Accumulating recent evidence strongly suggests that when human apoE is complexed with Aβ, the brain to blood clearance of Aβ is actually decreased compared to that of free Aβ.
“Accumulating recent evidence strongly suggests that when human apoE is complexed with Aβ, the brain to blood clearance of Aβ is actually decreased compared to that of free Aβ (Bell et al., 2007; Deane et al., 2008; Ito et al., 2007).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Bell et al., 2007
CLU levels are increased in proportion to APOE-ε4 allele dose, suggesting induction of clusterin in individuals with low APOE levels.
“Conversely, CLU levels are increased in proportion to APOE-ε4 allele dose suggesting an induction of clusterin in individuals with low APOE levels 35 .”
From Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (2009) · cites this paper as [35]
The Discussion describes an APOE-ε4 gene-dose effect on Alzheimer’s disease risk and amyloid deposition, not on CLU levels. The Results measure apoJ (clusterin) clearance in mice; no passage found links CLU levels to APOE-ε4 allele dose or suggests clusterin induction in people with low APOE levels. (LLM, conf=0.76)
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Self-citationapoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
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Self-citationThe role of microglia in amyloid clearance from the AD brain
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Understanding the functions and relationships of the glymphatic system and meningeal lymphatics
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ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
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Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease
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Self-citationNeurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease
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Self-citationEndothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier
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Role of Blood-Brain Barrier in Alzheimer’s Disease
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Clusterin in Alzheimer’s Disease: Mechanisms, Genetics, and Lessons From Other Pathologies
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Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
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Self-citationExercise benefits on Alzheimer’s disease: State-of-the-science
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ApoE facilitates the microglial response to amyloid plaque pathology
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Self-citationStrategies for transporting nanoparticles across the blood–brain barrier
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Self-citationCerebrovascular Effects of Apolipoprotein E: Implications for Alzheimer Disease
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SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells
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Self-citationHDL and cholesterol handling in the brain
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Neurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease
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Plasma clusterin and the risk of Alzheimer disease
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Mechanisms of Amyloid-β Peptide Clearance: Potential Therapeutic Targets for Alzheimer's Disease
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More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
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Self-citationFunctional Roles of the Interaction of APP and Lipoprotein Receptors
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- Authors
- Bell, R. D., Sagare, A. P., Friedman, A. E., Bedi, G. S., Holtzman, D. M., Deane, R., & Zlokovic, B. V.
- Affiliations
- University of Rochester Medicine (US)
- Washington University in St. Louis (US)
- Frank P Smith Laboratory for Neuroscience and Neurosurgical Research, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2007-05
- Volume
- 27
- Issue
- 5
- Pages
- 909-918
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC2853021
- OpenAlex
- W2034430748
- Cited by
- 670
- References
- 6
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 38 · 2023: 30 · 2022: 29 · 2021: 44 · 2020: 46 · 2019: 35 · 2018: 25 · 2017: 32 · 2016: 45 · 2015: 36 · 2014: 44 · 2013: 39 · 2012: 45
- FWCI
- 13.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion, public-domain)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R37AG023084, R37AG13956, R37AG013956)
- National Institute of Neurological Disorders and Stroke (R37NS034467, NS34467, R01NS034467)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- amyloid-beta, Alzheimer's disease, apolipoprotein E, clusterin, LRP1, megalin, amyloid-beta clearance, Aβ40, amyloid-beta 42, APOE3, lipid modification
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Biological Transport, Active, Blood-Brain Barrier, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Humans, Iodine Radioisotopes, Ligands, Mice, Inbred C57BL, Models, Statistical, Amyloid beta-Peptides, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Spectrometry, Mass, Electrospray Ionization, Clusterin, Mice
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