Mechanisms of Amyloid Angiopathy-Related Hemorrhage

描述（由申请人提供）：淀粉样血管病相关出血的机制淀粉样β肽（A-β）在脑血管中沉积（脑淀粉样血管病，CAA）是老年人的常见发现，在阿尔茨海默病患者中尤其突出。 CAA 最广泛认可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 (MMP) 是细胞外基质 (ECM) 降解蛋白酶家族，据推测在全身血管重塑中发挥作用，特别是 MMP-9（明胶酶 B）与多种血管病理有关。该假设将被检验，即 CAA 中脑血管中积聚的 A-β 会诱导血管 MMP-9 活性并导致自发性出血性中风的发生。具体目标 1 将检验以下假设：A-β 在体外刺激脑内皮细胞 (CEC) 和血管平滑肌细胞 (SMC) 中的 MMP-9 活性，从而增强 ECM 降解。具体目标 2 将探讨 c-Jun N 末端激酶 (JNK) 信号通路的作用以及随后转录因子 AP-1 的激活在 Ap 诱导的 CEC 和 SMC 体外 MMP-9 表达中的作用。具体目标 3 将检查富含淀粉样蛋白的血管中的蛋白水解微环境，以确定它是否有利于脑淀粉样血管病小鼠模型中的 MMP-9 表达和活性。具体目标 4 将检验以下假设：脑血管中 MMP-9 活性的增加（部分由 JNK/AP-1 信号通路介导）有助于老年 APPsw 小鼠自发性出血性中风的发生。本提案中的实验应有助于加深对 CAA 相关出血的分子发病机制的了解，从而有助于未来开发预防自发性脑出血的有效临床疗法。

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.