The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The 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 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]
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
“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]
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
“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]
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
“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]
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
“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]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
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
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
1 retracted
RETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
Sagare, A. P., Bell, R. D., Zhao, Z., Ma, Q., Winkler, E. A., Ramanathan, A., & Zlokovic, B. V. (2013) · Nature Communications · doi:10.1038/ncomms3932 · Cited by 589
Self-citationRetractedThe Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders
Zlokovic, B. V. (2008) · Neuron · doi:10.1016/j.neuron.2008.01.003 · Cited by 3,280
Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders
Zlokovic, B. V. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3114 · Cited by 2,969
Pericytes regulate the blood–brain barrier
Armulik, A., Genové, G., Mäe, M., Nisancioglu, M. H., Wallgard, E., Niaudet, C., He, L., Norlin, J., Lindblom, P., Strittmatter, K., et al. (2010) · Nature · doi:10.1038/nature09522 · Cited by 2,843
Pericytes are required for blood–brain barrier integrity during embryogenesis
Daneman, R., Zhou, L., Kebede, A. A., & Barres, B. A. (2010) · Nature · doi:10.1038/nature09513 · Cited by 2,128
Blood-brain barrier breakdown in the aging human hippocampus
Montagne, A., Barnes, S. R., Sweeney, M. D., Halliday, M. R., Sagare, A. P., Zhao, Z., Toga, A. W., Jacobs, R. E., Liu, C. Y., Amezcua, L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.032 · Cited by 2,102
Self-citationThe role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
Bell, R. D., Winkler, E. A., Sagare, A. P., Singh, I., LaRue, B., Deane, R., & Zlokovic, B. V. (2010) · Neuron · doi:10.1016/j.neuron.2010.09.043 · Cited by 1,448
Self-citationShibata, M., Yamada, S., Kumar, S. R., Calero, M., Bading, J., Frangione, B., Holtzman, D. M., Miller, C. A., Strickland, D. K., Ghiso, J., et al. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10498 · Cited by 1,413
Self-citationApolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293 · cited 11×
“Microvascular capillary length was quantified as the length of lectin-positive endothelial profiles (<6 mm in diameter) determined using the ImageJ plug-in length analysis tool from 15 images per specimen derived from five randomly selected fields in the cortex (420mm 420 mm) per section from three non-adjacent ( 100…”
BackgroundMethodResultInfluentialSelf-citation
Cited by
Sorted by citations
Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.188 · Cited by 3,076
Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,312
Self-citationEstablishment and Dysfunction of the Blood-Brain Barrier
Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. (2015) · Cell · doi:10.1016/j.cell.2015.10.067 · Cited by 1,670
Self-citationRole of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668
“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.”
BackgroundApolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
