{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:43:16Z","timestamp":1768509796137,"version":"3.49.0"},"posted":{"date-parts":[[2024,4,15]]},"group-title":"Neuroscience","reference-count":62,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The cell-type specific role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer\u2019s disease (AD) is not well characterized. In this study, we utilized a single-nucleus RNA sequencing dataset from Dorsolateral Prefrontal Cortex (DLFPC) of 424 donors from the Religious Orders Study and Memory and Aging Project (ROS\/MAP) to investigate the effect of 10 VEGF genes (\n                  <jats:italic>VEGFA, VEGFB, VEGFC, VEGFD, PGF, FLT1, FLT4, KDR, NRP1<\/jats:italic>\n                  , and\n                  <jats:italic>NRP2<\/jats:italic>\n                  ) on AD endophenotypes. Mean age of death was 89 years, among which 68% were females, and 52% has AD dementia. Negative binomial mixed models were used for differential expression analysis and for association analysis with \u03b2-amyloid load, PHF tau tangle density, and both cross-sectional and longitudinal global cognitive function. Intercellular VEGF-associated signaling was profiled using CellChat. We discovered prefrontal cortical\n                  <jats:italic>FLT1<\/jats:italic>\n                  expression was upregulated in AD brains in both endothelial and microglial cells. Higher\n                  <jats:italic>FLT1<\/jats:italic>\n                  expression was also associated with worse cross-sectional global cognitive function, longitudinal cognitive trajectories, and \u03b2-amyloid load. Similarly, higher endothelial\n                  <jats:italic>FLT4<\/jats:italic>\n                  expression was associated with more \u03b2-amyloid load. In contrast to the receptors,\n                  <jats:italic>VEGFB<\/jats:italic>\n                  showed opposing effects on \u03b2-amyloid load whereby higher levels in oligodendrocytes was associated with high amyloid burden, while higher levels in inhibitory neurons was associated with lower amyloid burden. Finally, AD cells showed significant reduction in overall VEGF signaling comparing to those from cognitive normal participants. Our results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons.\n                <\/jats:p>","DOI":"10.1101\/2024.04.12.589221","type":"posted-content","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T19:05:11Z","timestamp":1713207911000},"source":"Crossref","is-referenced-by-count":1,"title":["Association of 10 VEGF Family Genes with Alzheimer\u2019s Disease Endophenotypes at Single Cell Resolution"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9231-7093","authenticated-orcid":false,"given":"Yiyang","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia B","family":"Libby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Logan","family":"Dumitrescu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vilas","family":"Menon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie A.","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-7014","authenticated-orcid":false,"given":"Timothy J","family":"Hohman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024052404450610000_2024.04.12.589221v2.1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2008"},{"key":"2024052404450610000_2024.04.12.589221v2.2","first-page":"100030","article-title":"Pathologic sequelae of vascular cognitive impairment and dementia sheds light on potential targets for intervention","volume":"2","year":"2021","journal-title":"Cereb Circ-Cogn Behav"},{"key":"2024052404450610000_2024.04.12.589221v2.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1282-8"},{"key":"2024052404450610000_2024.04.12.589221v2.4","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3390\/ijms20020257","article-title":"Decreased Serum Brain-Derived Neurotrophic Factor (BDNF) Levels in Patients with Alzheimer\u2019s Disease (AD): A Systematic Review and Meta-Analysis","volume":"20","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2024052404450610000_2024.04.12.589221v2.5","first-page":"455","article-title":"Vascular endothelial growth factor (VEGF) \u2013 key factor in normal and pathological angiogenesis","volume":"59","year":"2018","journal-title":"Rom J Morphol Embryol"},{"key":"2024052404450610000_2024.04.12.589221v2.6","doi-asserted-by":"crossref","unstructured":"Silva T. 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