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Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease
Open accessAbstract
The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 ( APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD ( APOE4 > APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.
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“The loss of pericytes is probably caused by increased expression of friend leukemia virus integration 1 (Fli-1) after being activated.503”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [503]
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“Human APOE4 carriers compared with non-carriers develop accelerated BBB breakdown and pericyte degeneration (229, 230, 267, 516, 691, 702), early neurovascular dysfunction (494, 531, 584), impaired cerebrovascular reactivity (227, 568), and diminished regional BBB uptake of glucose (457, 486).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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“These blood-derived proteins are often found colocalized with A 𝛃 (267, 509, 527) and are more pronounced in APOE4 carriers compared with noncarriers (230, 267, 516, 691).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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“Post mortem studies show vascular capillary leakages of blood-derived proteins in the prefrontal and entorhinal cortex and hippocampus of AD patients including perivascular accumulation of fibrin(ogen), thrombin, albumin, immunoglobulin G (IgG), and iron-containing proteins such as hemosiderin (120, 125, 230, 267, 412, 509, 527, 691).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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“Further evidence of BBB breakdown in AD is repeatedly observed in numerous post mortem human studies showing reduced capillary length and microvascular degeneration with diminished TJ protein expression, capillary basement membrane alterations, and brain endothelial degeneration (36, 40, 230, 516, 527, 656).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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“Brain pericytes and endothelial cells in AD APOE4 carriers exhibit increased activity of BBB-degrading CypA-MMP-9 pathway compared with noncarriers (230).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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“Activation of CypAMMP-9 pathway associated with BBB breakdown has also been shown in human APOE4 carriers compared with noncarriers, as indicated by CSF (229) and post mortem BBB tissue (230) analyses.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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“In AD patients, BBB damage is associated with loss of pericytes,503 while the decrease in pericytes is followed by an increase in activated microglia.504”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [503]
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“For example, APOE4 carriers at risk for sporadic AD compared with non-carriers develop BBB breakdown (229, 230, 267, 516, 691, 702) and early cerebrovascular dysfunction (227, 457, 486, 494, 531, 568, 584)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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“Activation of CypA-MMP-9 pathway associated with BBB breakdown has been also shown in human APOE4 carriers by cerebrospinal fluid (CSF) analysis (229) and post mortem brain tissue analysis (230, 267).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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“Similarly, PDGFR 𝛃 immunostaining revealed significantly reduced pericyte coverage of brain capillaries as well as reduced pericyte numbers in AD cortex and hippocampus compared with control brains (527), which is accelerated by APOE4 gene (230).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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“AD brain microvessels also exhibit reduced levels of LRP1, a major A 𝛃 clearance receptor at the BBB (137, 152, 230, 410, 535).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [230]
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Metadata
- Authors
- Halliday, M. R., Rege, S. V., Ma, Q., Zhao, Z., Miller, C. A., Winkler, E. A., & Zlokovic, B. V.
- Affiliations
- University of Southern California (US)
- University of California, San Francisco (US)
- Department of Physiology and Biophysics, Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2015-03-11
- Volume
- 36
- Issue
- 1
- Pages
- 216-227
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC4758554
- OpenAlex
- W2055467683
- Cited by
- 649
- References
- 41
- Citations by year
- 2026: 54 · 2025: 62 · 2024: 72 · 2023: 63 · 2022: 69 · 2021: 85 · 2020: 71 · 2019: 49 · 2018: 41 · 2017: 35 · 2016: 29 · 2015: 18
- FWCI
- 21.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Scholars Repository - LLU (Loma Linda University) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG023084, R01AG039452, R37AG023084, P50-AG05142, P50AG005142, R37AG23084, RF1AG039452)
- National Institute of Neurological Disorders and Stroke (R37NS034467, R01NS034467, R37NS34467)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, APOE ε4, blood-brain barrier disruption, pericyte degeneration, cyclophilin A, MMP-9, LRP1, IgG, fibrin, inflammatory cytokines, endothelial cells, APOE ε4 carriers
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Blood-Brain Barrier, Cell Count, Endothelium, Vascular, Female, Humans, Male, Cohort Studies, Protein Isoforms, Pericytes, Apolipoprotein E4
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