Mechanisms of Amyloid Angiopathy-Related Hemorrhage

淀粉样蛋白血管病变相关出血的机制淀粉样蛋白- β肽（a - β）在脑血管中的沉积（脑淀粉样蛋白血管病变，CAA）在老年人中很常见，在阿尔茨海默病患者中尤为突出。CAA最常见的并发症之一是原发性非外伤性脑出血；然而，caa相关出血的分子发病机制尚不清楚。基质金属蛋白酶（MMPs）是一个细胞外基质（ECM）降解蛋白酶家族，被认为在全身血管重构中发挥作用，尤其是MMP-9（明胶酶B），与多种血管病变有关。在CAA中，a - β在脑血管中积累，诱导血管MMP-9活性，并参与自发性出血性中风的发生，这一假设将得到验证。特异性目的1将验证a - β在体外刺激脑内皮细胞（CECs）和血管平滑肌细胞（SMCs）中MMP-9活性，增强ECM降解的假设。特异性目的2将探讨c-Jun n -末端激酶（JNK）信号通路和随后的转录因子AP-1激活在体外CECs和SMCs中ap诱导的MMP-9表达中的作用。特异性目的3将检查淀粉样蛋白装载血管中的蛋白水解微环境，以确定它是否有利于脑淀粉样蛋白血管病小鼠模型中MMP-9的表达和活性。特异性Aim 4将验证JNK/AP-1信号通路部分介导的脑血管中MMP-9活性的增加有助于老年APPsw小鼠自发性出血性中风的发生。本课题的实验将有助于进一步了解caa相关脑出血的分子发病机制，从而有助于未来开发有效的临床治疗方法来预防自发性脑出血。

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.