Browsing by Subject "AD"
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Item Endothelial Vcam-1 As A Marker for Cerebrovascular Inflammation in Alzheimer’S Disease(2023-05) Salian, VrishaliAlzheimer’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.Item Quantification and Analysis of Tau Protein Effects on Microtubule Dynamics in Mammalian (LLC-PK1) Cells(2020-07) Doersch, AlexandraOverall, we found that multiple biophysical properties of tau protein affect MT dynamics in LLC-PK1 cells; various isoforms exhibit differential effects. 2N4R tau exhibits MT tip avoidance (~200 nm) during growth that is lost for 0N4R tau. 2N4R and 0N4R tau phenocopy MTAs to make MTs less dynamic via different processes. We propose 2N4R tau has at least two binding sites, one of higher and one of lower affinity, resulting in KD=0.31 µM that preferentially associates with GDP-tubulin lattice to enable growing tip avoidance. 0N4R tau loses access to higher but retains lower affinity binding, resulting in KD=3.2 µM. Uniquely, 0N4R P301L tau does not bind to MTs (KD>>10 µM), indicating loss of both higher and lower affinity binding, perhaps due to induced conformation changes. Possible implications for tauopathies include the decreased ability of 0N4R P301L tau to bind to MTs, which may promote disease-associated progression toward tau oligomerization.