Mechanisms of Amyloid Angiopathy-Related Hemorrhage

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Mechanisms of Amyloid Angiopathy-Related Hemorrhage The deposition of amyloid-beta peptide (A-beta) in cerebral vessels (cerebral amyloid angiopathy, CAA) is a common finding in the elderly, and especially prominent in patients with Alzheimer's disease. One of the most widely recognized complications of CAA is primary nontraumatic intracerebral hemorrhage; however, the molecular pathogenesis of CAA-related hemorrhage is poorly understood. The matrix metalloproteinases (MMPs), a family of extracellular matrix (ECM)-degrading proteinases, have been postulated to play a role in systemic vascular remodeling, and MMP-9 (gelatinase B), in particular, has been implicated in a variety of vascular pathologies. The hypothesis will be tested that A-beta, which accumulates in cerebral blood vessels in CAA, induces vascular MMP-9 activity and contributes to the development of spontaneous hemorrhagic stroke. Specific Aim 1 will test the hypothesis that A-beta stimulates MMP-9 activity in cerebral endothelial cells (CECs) and vascular smooth muscle cells (SMCs) in vitro, enhancing ECM degradation. Specific Aim 2 will explore the role of the c-Jun N-terminal Kinase (JNK) signaling pathway and subsequent activation of the transcription factor, AP-1, in Ap-induced MMP-9 expression in CECs and SMCs in vitro. Specific Aim 3 will examine the proteolytic microenvironment in amyloid-laden vessels to determine if it favors MMP-9 expression and activity in a mouse model of cerebral amyloid angiopathy. Specific Aim 4 will test the hypothesis that increased MMP-9 activity in cerebral vessels, mediated in part by the JNK/AP-1 signaling pathway, contributes to the development of spontaneous hemorrhagic strokes in aged APPsw mice. Experiments in this proposal should lead to an enhanced understanding of the molecular pathogenesis of CAA-related hemorrhage, and thus aid the future development of effective clinical therapies for the prevention of spontaneous intracerebral hemorrhage.