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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Loss of pericytes is probably caused by increased expression of Fli-1 after activation.
“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]
The section on cyclophilin A and MMP-9 accumulation reports that pericyte loss correlates with activation of the CypA–MMP-9 pathway, but says the nature of that relationship cannot be determined from the postmortem analysis. It does not identify Fli-1 or support increased Fli-1 expression as the cause of pericyte loss. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHuman APOE4 carriers compared with non-carriers develop accelerated BBB breakdown and pericyte degeneration, early neurovascular dysfunction, impaired cerebrovascular reactivity, and diminished regional BBB uptake of glucose.
“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]
The Discussion reports accelerated pericyte degeneration and BBB breakdown in human AD APOE4 carriers compared with AD APOE3 carriers. The citing sentence omits the AD restriction, so this paper does not establish that finding for APOE4 carriers generally. Its other claims have separate citation groups and are not attributed to this source here. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThese blood-derived proteins are often found colocalized with Aβ and are more pronounced in APOE4 carriers compared with noncarriers.
“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]
The Results section on accelerated blood–brain barrier breakdown reports greater fibrin deposits and extravascular IgG in AD APOE4 carriers than in AD APOE3 carriers. Our copy does not report that these proteins colocalize with Aβ, and the comparison is specifically among patients with Alzheimer’s disease, not carriers and noncarriers generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPost 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, and iron-containing proteins such as hemosiderin.
“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]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn Alzheimer's disease, post mortem human studies show reduced capillary length and microvascular degeneration with diminished tight junction protein expression, capillary basement membrane alterations, and brain endothelial degeneration.
“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]
The Results section on pericyte degeneration and microvascular reductions reports shorter total capillary length in post mortem AD samples, and the BBB breakdown section reports vascular leakage. The Discussion mentions tight-junction and basement-membrane protein degradation in APOE4 mice, not measurements of those changes in the human samples; the paper also does not establish brain endothelial degeneration in those samples. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
In Alzheimer's disease APOE4 carriers, brain pericytes and endothelial cells exhibit increased activity of the BBB-degrading CypA-MMP-9 pathway compared with noncarriers.
“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]
The Discussion reports greater CypA and MMP-9 accumulation in pericytes and endothelial cells of AD APOE4 carriers than in AD APOE3 carriers. The paper interprets this as suggestive of enhanced BBB-degrading pathway activation; it does not establish increased pathway activity in those human cells as an unqualified finding. (LLM, conf=0.86)
Experimental — accuracy not yet measuredActivation of the CypA-MMP-9 pathway associated with blood-brain barrier breakdown has been shown in human APOE4 carriers compared with noncarriers, as indicated by CSF and post mortem blood-brain barrier tissue analyses.
“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]
The postmortem tissue findings (Abstract; Discussion) show greater CypA and MMP-9 accumulation and BBB damage in AD APOE4 carriers than in AD APOE3 carriers. The paper describes enhanced pathway activation as suggested by those findings, rather than directly demonstrated, and its postmortem comparison is limited to people with AD. The Discussion also reports earlier CSF findings in cognitively normal carriers, but the citing sentence assigns those to a separate citation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn AD patients, BBB damage is associated with loss of pericytes, and decrease in pericytes is followed by an increase in activated microglia.
“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]
APOE4 carriers at risk for sporadic AD compared with non-carriers develop BBB breakdown and early cerebrovascular dysfunction.
“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]
Activation of the CypA-MMP-9 pathway associated with blood-brain barrier breakdown has been shown in human APOE4 carriers by cerebrospinal fluid analysis and post mortem brain tissue analysis.
“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]
PDGFRβ immunostaining revealed significantly reduced pericyte coverage of brain capillaries as well as reduced pericyte numbers in AD cortex and hippocampus compared with control brains, which is accelerated by APOE4 gene.
“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]
In Alzheimer's disease, brain microvessels exhibit reduced levels of LRP1, a major amyloid-beta clearance receptor at the blood-brain barrier.
“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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“The loss of pericytes is probably caused by increased expression of friend leukemia virus integration 1 (Fli-1) after being activated.(503) Fli-1 is an important regulator of inflammation and was reported to enhance the proinflammatory cytokine secretion from lung pericytes.”
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“In this context, carriers of apolipoprotein 4 (APOE4) allele, a major risk factor for AD, present with pericyte degeneration and associated BBB breakdown [42], which has been recently associated with cognitive decline, independent of AD pathology [43].”
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- 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
- Health Sciences › Medicine › Physiology › 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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