Vascular deposition of amyloid-beta-peptide (Abeta) occurs during normal aging and is accelerated in Alzheimer's Disease (AD) and related disorders such as hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), a form of cerebral amyloid angiopathy (CAA). In CAA, HCHWA-D and AD increased vascular deposition of Abeta is associated with invasion of monocyte/macrophages in the vessel wall and activated microglial cells in the parenchyma. Relatively little is known about the cellular and molecular mechanisms in cerebral vasculature that may play a role in Abeta-mediated accumulation of peripheral inflammatory cells. Recent studies indicated that peripheral hematopoietic cells (i.e., monocytes) can cross the blood-brain barrier (BBB). Our studies shown that Abeta increases diapedesis of leukocytes across the vascular endothelium, and induces migration of monocytes across the human BBB in vitro, blocked by antibodies to PECAM-1 ( a cell junction molecule ) and RAGE (putative receptor for A beta). The central hypothesis is that interaction of Abeta with its putative receptor(s) in the brain vascular endothelium brings about cellular signaling which results in the modulation of PECAM-1 to allow migration of monocytes across the BBB. It is further hypothesized, that migration of monocytes is exaggerated across cerebral vasculature in AD and aged non-human primates, presumably due to increased expression and/or redistribution of Abeta receptors at the BBB. To test this hypothesis we will determine (1) the effect of Abeta on adhesion and migration of monocytes across monolayer of human brain microvascular endothelial cells (HBMVEC); (2) whether Abeta causes increased migration of monocytes in HBMVEC from geriatric and AD cases; (3) the role of p21/ras, MAP kinase, NF-kappaB,, RAGE and PAF in Abeta induced cellular signaling, using pharmacological inhibitors and over-expressing or knocking out genes by transfection of HBMVEC, and (4) the mechanisms of Abeta-induced adhesion and diapedesis of leukocytes across the vessel wall in transgenic (Tg) CC HCHWA-D mice and Tg vascular RAGE mice. Proposed studies will provide a novel insight into the mechanisms of Abeta-induced migration of hematopoietic cells across the vessel wall and the BB and will provide a molecular basis for the therapeutic rationale to modify Abeta- induced inflammatory reactions in the aging brain to ameliorate the neuronal injury.
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