Salian, Vrishali2023-09-192023-09-192023-05https://hdl.handle.net/11299/256939University of Minnesota M.S. thesis. May 2023. Major: Pharmaceutics. Advisor: Karunya Kandimalla. 1 computer file (PDF); ix, 67 pages.Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Aβ) deposition and neurofibrillary tangles are two of the key pathological hallmarks of familial and sporadic forms of AD. Cerebrovascular inflammation is emerging as a third core feature of AD pathology. Activation of inflammatory signaling pathways have been observed in AD patients and AD mouse models. Cerebrovascular inflammation, a consequence of the ongoing AD pathogenesis, could eventually drive and accelerate AD progression. We have demonstrated that inflammatory pathway is upregulated in AD patient brains. Moreover, cerebrovascular inflammation is augmented in AD transgenic mouse model (APP/PS1). The expression of vascular cell adhesion molecule-1 (VCAM-1), a cerebrovascular inflammatory marker expressed on the blood brain barrier (BBB) endothelial cells, was found to be upregulated in APP/PS1 mice as determined by dynamic SPEC/CT imaging. We have further shown that Aβ42 exposure increased VCAM-1 expression in human cerebral microvascular endothelial (hCMEC/D3) cells. Despite this compelling evidence, pathophysiological mechanisms driving VCAM-1 expression in AD remains to be poorly understood. We investigated the molecular mechanisms underlying Aβ42 mediated increase in VCAM-1 expression using reverse phase protein array assay (RPPA), where we identified several proteins related to inflammation signaling, which are perturbed by Aβ42 peptide. Our studies have shown that Aβ42 exposure increases VCAM-1 expression through the Src/p38/MEK signaling pathway in hCMEC/D3 cell monolayers. Together, these observations show that Aβ42 exposure triggers cerebrovascular inflammation by increasing VCAM-1 expression, which could be mediated by the Src/p38/MEK signaling pathway.enADAβBBBcerebrovascular inflammationVCAM-1Thesis or Dissertation