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We and others have recently identified a novel functionally distinct subset of BBB pericytes (PCs). In the present study, we sought to determine whether these PC subsets differentially contribute to AD\u2010associated pathologies by immunohistochemistry and amyloid beta (A\u03b2) peptidomics. We demonstrated that a disease\u2010associated PC subset (PC2) expanded in AD patients compared to age\u2010matched, cognitively unimpaired controls. Surprisingly, we found that this increase in the percentage of PC2 (%PC2) was correlated <jats:italic>negatively<\/jats:italic> with BBB breakdown in AD patients, unlike in natural aging or other reported disease conditions. The higher %PC2 in AD patients was also correlated with a lower A\u03b242 plaque load and a lower A\u03b242:A\u03b240 ratio in the brain as determined by immunohistochemistry. Colocalization analysis of multicolor confocal immunofluorescence microscopy images suggests that AD patient with low %PC2 have higher BBB breakdown due to internalization of A\u03b242 by the physiologically normal PC subset (PC1) and their concomitant cell death leading to more vessels without PCs and increased plaque load. On the contrary, it appears that PC2 can secrete cathepsin D to cleave and degrade A\u03b2 built up outside of PC2 into more soluble forms, ultimately contributing to less BBB breakdown and reducing A\u03b2 plaque load. Collectively our data shows functionally distinct mechanisms for PC1 and PC2 in high A\u03b2 conditions, demonstrating the importance of correctly identifying these populations when investigating the contribution of neurovascular dysfunction to AD pathogenesis.<\/jats:p>","DOI":"10.1111\/bpa.13282","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T07:51:35Z","timestamp":1719474695000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Functionally distinct pericyte subsets differently regulate amyloid\u2010\u03b2 deposition in patients with Alzheimer's disease"],"prefix":"10.1111","volume":"35","author":[{"given":"Diana G.","family":"Bohannon","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Cell Biology Eastern Virginia Medical School  Norfolk Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Cell Biology Eastern Virginia Medical School  Norfolk Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid R.","family":"Okhravi","sequence":"additional","affiliation":[{"name":"Glennan Center for Geriatrics and Gerontology Eastern Virginia Medical School  Norfolk Virginia USA"},{"name":"Integrated Neurodegenerative Disorders Center Eastern Virginia Medical School  Norfolk Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunhee C.","family":"Lee","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc  Tarrytown New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1550-7475","authenticated-orcid":false,"given":"Christopher Lawrence","family":"De Jesus","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Physiology New York University Grossman School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Neubert","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Physiology New York University Grossman School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agueda A.","family":"Rostagno","sequence":"additional","affiliation":[{"name":"Department of Pathology New York University Grossman School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge A.","family":"Ghiso","sequence":"additional","affiliation":[{"name":"Department of Pathology New York University Grossman School of Medicine  New York New York USA"},{"name":"Department of Psychiatry New York University Grossman School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9964-185X","authenticated-orcid":false,"given":"Woong\u2010Ki","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Cell Biology Eastern Virginia Medical School  Norfolk Virginia USA"},{"name":"Integrated Neurodegenerative Disorders Center Eastern Virginia Medical School  Norfolk Virginia USA"},{"name":"Division of Microbiology Tulane National Primate Research Center  Covington Louisiana USA"},{"name":"Department of Microbiology and Immunology Tulane University School of Medicine  New Orleans Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,27]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Alzheimer's Association.Alzheimer's disease facts and figures.2021."},{"key":"e_1_2_10_3_1","unstructured":"WolkDA DickersonBC.Clinical features and diagnosis of Alzheimer disease. 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