{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T14:16:14Z","timestamp":1783433774907,"version":"3.54.6"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Recent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor-1 (VEGFR-1\/FLT1) and in AD brain. Increased expression of VEGFR1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between increased VEGFR-1 expression in AD pathogenesis. In this study, we explored the potential role of VEGFR-1 expression in neurons on AD pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To confirm VEGFR1 expression in AD brains, we first performed immunostaining in AD brain sections (AD - Braak stage V-VI, and normal controls - Braak 0-II). And to determine a potential detrimental role of neuronal VEGFR1 expression on AD associated pathologies, we exposed SH-SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O\n                      <jats:sub>2<\/jats:sub>\n                      ) or 5 \u03bc A\u03b21-42 oligomers or fibrils for 24, 28 and 72hrs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, we found preferential staining of VEGFR-1 in the neuropil and neuronal cell bodies both in AD and Control hippocampus and increased VEGFR-1 immunoreactivity in dystrophic neuritic processes in the vicinity of Thio-S positive amyloid plaques in AD brains. And treatment of SH-SY5Y human neuroblastoma cell line and mouse primary neurons, with either hypoxia conditions or A\u03b21-42 oligomers, resulted in increased VEGFR-1 expression and cleaved caspase 3 activation, leading to neuronal toxicities\/cell death. Similarly, treatment with A\u03b21-42 fibrils also increased VEGFR-1 and cleaved caspase 3 protein levels in the SH-SY5Y cells whereas treatment with A\u03b21-42 monomers had no effect on VEGFR-1 expression. In addition, we show that over-expression of VEGFR-1 intracellular domains in SH-SY5Y cells directly induced neuronal toxicities and importantly, siRNA-mediated knockdown of VEGFR-1 in neurons prevented the hypoxia, A\u03b21-42 oligomer and A\u03b21-42 fibril-induced toxicities and cell death phenotypes. Treatment with either hypoxia or A\u03b21-42 oligomers also reduced expression of cell survival genes including VEGFR-2 and Hippo pathway YAP1 and siRNA-mediated VEGFR-1 knockdown in the neurons normalized expression of both VEGFR-2 and YAP1. Using differential gene expression analysis, we demonstrated upregulation of several inflammatory\/interferon-stimulated genes (ISGs) as well as increased expression of genes involved in activation of oxidative stress and cell death pathways in response to A\u03b21-42 oligomers treatment in mouse primary neurons. And siRNA-mediated VEGFR-1 knockdown in the mouse primary neurons, reduced gene expression of both the ISGs and oxidative stress\/cell death pathways in response to A\u03b21-42 oligomer treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>In summary, these results show that siRNA-mediated knockdown of VEGFR-1 in neurons significantly prevented hypoxia, A\u03b21-42 oligomer and A\u03b21-42 fibril-induced cellular toxicities and cell death phenotypes, indicating a potential detrimental role of aberrant VEGFR-1 expression and signaling in response to AD associated pathologies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1799391","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T06:10:08Z","timestamp":1780035008000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Vascular endothelial growth factor receptor-1 (VEGFR-1) knock-down is protective against hypoxia, A\u03b21-42 oligomer and A\u03b21-42 fibril -induced neuronal cell death: implications in AD pathogenesis"],"prefix":"10.3389","volume":"20","author":[{"given":"Ramcharan Singh","family":"Angom","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zonghua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hari Krishnareddy","family":"Rachamala","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Castanedes-Casey","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanmay","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trisha","family":"Chakravarty","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamit","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debabrata","family":"Mukhopadhyay","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pritam","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic Florida","place":["Jacksonville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"903047","DOI":"10.3389\/fcell.2022.903047","article-title":"Vascular endothelial growth factor receptor-1 modulates hypoxia-mediated endothelial senescence and cellular membrane stiffness via YAP-1 pathways.","volume":"10","author":"Angom","year":"2022","journal-title":"Front. 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