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It is unknown whether systemic vascular dysfunction occurs prior to the development of AD, if this occurs in a sex-dependent manner, and whether endothelial cells play a role in the deposition of amyloid beta (A\u03b2) peptides. We hypothesized that vascular dysfunction occurs prior to the onset of amyloid pathology, thus escalating its progression. Furthermore, endothelial cells from female mice will present with an exacerbated formation of A\u03b2 peptides due to an exacerbated pressure pulsatility. To test this hypothesis, we used a double transgenic mouse model of early-onset AD (APPswe\/PSEN1dE9). We evaluated hippocampus-dependent recognition memory and the cardiovascular function by echocardiography and direct measurements of blood pressure through carotid artery catheterization. Vascular function was evaluated in resistance arteries, morphometric parameters in the aortas, and immunofluorescence in the hippocampus and aortas. We observed that endothelial dysfunction occurred prior to the onset of amyloid pathology irrespective of sex. However, during the onset of amyloid pathology, only female APP\/PS1 mice had vascular stiffness in the aorta. There was elevated A\u03b2 deposition which colocalized with endothelial cells in the hippocampus from female APP\/PS1 mice. Overall, these data showed that vascular abnormalities may be an early marker, and potential mediator of AD, but exacerbated aortic stiffness and pressure pulsatility after the onset of amyloid pathology may be associated with a greater burden of A\u03b2 formation in hippocampal endothelial cells from female but not male APP\/PS1 mice.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s11357-024-01213-0","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T14:02:14Z","timestamp":1718114534000},"page":"5517-5536","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Vascular dysfunction occurs prior to the onset of amyloid pathology and A\u03b2 plaque deposits colocalize with endothelial cells in the hippocampus of female APPswe\/PSEN1dE9 mice"],"prefix":"10.1007","volume":"46","author":[{"given":"Emily W.","family":"Waigi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laena","family":"Pernomian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexia M.","family":"Crockett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago J.","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Paul","family":"Townsend","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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