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）在脑血管中的沉积（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为突出。CAA最广泛的并发症之一是原发性非创伤性脑出血，然而，CAA相关出血的分子发病机制知之甚少。基质金属蛋白酶（MMP）是细胞外基质（ECM）降解蛋白酶的一个家族，已被假定在系统性血管重塑中起作用，特别是MMP-9（明胶酶B），已被牵涉到多种血管病理。将检验假设，即CAA中脑血管中蓄积的A-β诱导血管MMP-9活性并促成自发性出血性卒中的发展。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，增强ECM降解。具体目标2将探讨c-Jun N-末端激酶（JNK）信号通路的作用和随后激活的转录因子，AP-1，在AP诱导的MMP-9表达在CEC和SMCs在体外。具体目标3将检查充满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：部分由JNK/AP-1信号通路介导的脑血管中MMP-9活性增加有助于老年APPsw小鼠自发性出血性卒中的发展。本实验的建议应导致CAA相关出血的分子发病机制的理解，从而有助于未来发展有效的预防自发性脑出血的临床治疗。

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.