Deficiency in Mural Vascular Cells Coincides with Blood–Brain Barrier Disruption in A lzheimer's Disease
Open accessAbstract
Neurovascular dysfunction contributes to A lzheimer's disease ( AD ). Cerebrovascular abnormalities and blood–brain barrier ( BBB ) damage have been shown in AD . The BBB dysfunction can lead to leakage of potentially neurotoxic plasma components in brain that may contribute to neuronal injury. Pericytes are integral in maintaining the BBB integrity. Pericyte‐deficient mice develop a chronic BBB damage preceding neuronal injury. Moreover, loss of pericytes was associated with BBB breakdown in patients with amyotrophic lateral sclerosis. Here, we demonstrate a decrease in mural vascular cells in AD , and show that pericyte number and coverage in the cortex and hippocampus of AD subjects compared with neurologically intact controls are reduced by 59% and 60% ( P < 0.01), and 32% and 33% ( P < 0.01), respectively. An increase in extravascular immunoglobulin G ( IgG ) and fibrin deposition correlated with reductions in pericyte coverage in AD cases compared with controls; the Pearson's correlation coefficient r for the magnitude of BBB breakdown to IgG and fibrin vs. reduction in pericyte coverage was −0.96 ( P < 0.01) and −0.81 ( P < 0.01) in the cortex, respectively, and −0.86 ( P < 0.01) and −0.98 ( P < 0.01) in the hippocampus, respectively. Thus, deficiency in mural vascular cells may contribute to disrupted vascular barrier properties and resultant neuronal dysfunction during AD pathogenesis.
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These 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 [527]
The Results section ('Increased Aβ deposition correlates with pericyte reduction in AD'; page not provided) reports overlap between Aβ and IgG immunostaining, and the Discussion describes Aβ deposits overlapping with blood-derived proteins such as IgG. The paper does not report that these deposits are more pronounced in APOE4 carriers than noncarriers; its reported comparisons are between AD cases and neurologically intact controls. (LLM, conf=0.87)
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 [527]
The Results (page unavailable) report extravascular IgG and fibrin in the frontal cortex and hippocampus of post-mortem AD cases; the Discussion also mentions fibrinogen deposits in AD tissue. The paper does not establish the claimed leakage in entorhinal cortex or albumin deposits in AD. Its Discussion mentions thrombin and hemosiderin in post-mortem ALS cases, not AD cases. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPDGFRβ 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 [527]
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- Authors
- Sengillo, J. D., Winkler, E. A., Walker, C. T., Sullivan, J. S., Johnson, M., & Zlokovic, B. V.
- Affiliations
- University of Southern California (US)
- University of Rochester Medicine (US)
- Center for Neurodegeneration and Regeneration Zilkha Neurogenetic Institute University of Southern California Los Angeles CA
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2012-11-28
- Volume
- 23
- Issue
- 3
- Pages
- 303-310
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC3628957
- OpenAlex
- W1957400240
- Cited by
- 553
- References
- 45
- Citations by year
- 2026: 25 · 2025: 42 · 2024: 67 · 2023: 54 · 2022: 65 · 2021: 54 · 2020: 60 · 2019: 33 · 2018: 32 · 2017: 30 · 2016: 28 · 2015: 31 · 2014: 19 · 2013: 11
- FWCI
- 9.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health (NS34467)
- National Institute on Aging (R01AG023084, R01AG039452, AG23084, R37AG023084, AG039452, RF1AG039452)
- National Institute of Neurological Disorders and Stroke (R37NS034467, NS34467, R01NS034467)
- 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, blood-brain barrier disruption, pericytes, neurovascular dysfunction, cerebral microvasculature, fibrin deposition, hippocampus, cerebral cortex, pericyte coverage
- MeSH terms
- Aged, Alzheimer Disease, Blood Proteins, Blood Vessels, Blood-Brain Barrier, Cell Count, Cerebral Cortex, Cerebrovascular Circulation, Female, Fibrin, Fluorescent Antibody Technique, Hippocampus, Humans, Immunoglobulin G, Image Processing, Computer-Assisted, Male, Middle Aged, Amyloid beta-Peptides, Pericytes, Myocytes, Smooth Muscle
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