Project# 5: Oligomeric AB and Inflammation in Neurovascular Pathogenesis in AD In Alzheimer disease (AD) beta-amyloid (AB) deposition in the cerebrovasculature is common and there is increasing 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-like receptor 4 on the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in the BBB. The resulting inflammatory response contributes to the deposition of fibrillar AB and induces a cerebrovascular inflammatory cascade that encompasses adjacent perivascular macrophages and astrocytes. The resulting chronic expression of proinflammatory cytokines, increases inflammatory cell adhesion molecules on endothelial cells, and attenuates trophic factor receptor-mediated signaling in the neurovascular unit. Moreover, because of the chronic exposure to 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 inflammation exacerbates the inflammatory state of the cerebrovascular system. The role of oligomeric forms of AB in inflammation and degeneration in the cerebrovasculature remains largely unknown due to the lack of suitable animal models to investigate the pathological lesions associated with vascular deposition of AB. We will utilize APP2576 and Tg-SwDI mice because collectively they develop the broad spectrum of cerebrovascular pathology that are found in AD.
Aim 1 : Do oligomeric forms of AB correlate with the onset of inflammation in the cerebrovasculature in AD, Down Syndrome (DS), and APP/Tg mice? Aim 2: Do oligomeric forms of AB activate the CD14-TLR4 receptor complex? Do oligomeric forms of AB activate ECs and VSMCs? Do oligomeric forms of AB inhibit growth factor signaling in ECs and VSMCs? Aim 3: Does chronic systemic inflammation exacerbate cerebrovascular deposition of oligomeric AB and increase cerebrovascular inflammation? Aim 4: Therapeutic Strategies: Can anti-inflammatory approaches attenuate the inflammatory-induced adverse events in the cerebrovasculature in APP/Tg mice? Can transfected mesenchymal stem cells (MSCs) expressing a single chain anti-AB antibody attenuate AB oligomer-mediated cerebrovascular inflammation and degeneration?
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