Project# 5: Oligomeric AB and Inflammation in Neurovascular Pathogenesis in ADIn Alzheimer disease (AD) beta-amyloid (AB) deposition in the cerebrovasculature is common and there isincreasing recognition that dysfunction in the BBB plays a critical role in many neurodegenerative diseases,including AD. The focus of this project is on the hypothesis that oligomer forms of AB activate CD-14-toll-likereceptor 4 on the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in the BBB. The resultinginflammatory response contributes to the deposition of fibrillar AB and induces a cerebrovascular inflammatorycascade that encompasses adjacent perivascular macrophages and astrocytes. The resulting chronic expression ofproinflammatory cytokines, increases inflammatory cell adhesion molecules on endothelial cells, and attenuatestrophic factor receptor-mediated signaling in the neurovascular unit. Moreover, because of the chronic exposureto AB oligomers and the subsequent deposition of fibrillar AB in vascular elements, these cells remain in a'primed state' ready to be further activated. A secondary hypothesis is that chronic systemic inflammationexacerbates the inflammatory state of the cerebrovascular system. The role of oligomeric forms of AB ininflammation and degeneration in the cerebrovasculature remains largely unknown due to the lack of suitableanimal models to investigate the pathological lesions associated with vascular deposition of AB. We will utilizeAPP2576 and Tg-SwDI mice because collectively they develop the broad spectrum of cerebrovascular pathologythat are found in AD.
Aim 1 : Do oligomeric forms of AB correlate with the onset of inflammation in thecerebrovasculature in AD, Down Syndrome (DS), and APP/Tg mice? Aim 2: Do oligomeric forms of ABactivate the CD14-TLR4 receptor complex? Do oligomeric forms of AB activate ECs and VSMCs? Dooligomeric forms of AB inhibit growth factor signaling in ECs and VSMCs? Aim 3: Does chronic systemicinflammation exacerbate cerebrovascular deposition of oligomeric AB and increase cerebrovascular inflammation?Aim 4: Therapeutic Strategies: Can anti-inflammatory approaches attenuate the inflammatory-induced adverseevents in the cerebrovasculature in APP/Tg mice? Can transfected mesenchymal stem cells (MSCs) expressing asingle chain anti-AB antibody attenuate AB oligomer-mediated cerebrovascular inflammation and degeneration?
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