AMYLOID INDUCED CEREBROENDOTHELIAL DEGENERATION

描述(改编自《调查者摘要》)：最重要的 中风的危险因素是年龄。年龄也是最重要的风险因素 阿尔茨海默病(AD)。脑实质和脑内淀粉样蛋白沉积 脑血管系统在正常衰老时发生，特别是在AD时。淀粉样蛋白 脑血管中的沉积是导致出血性和 伴或不伴AD的老年人中的缺血性卒中。的主要组成部分 脑血管中的淀粉样物是一种小肽，即淀粉样蛋白B (A、B)。AB对培养和培养的脑内皮细胞(CECs)有细胞毒作用 活着。A、8的这种作用可能与年龄相关的发育有关 脑淀粉样血管病(CAA)。AB细胞毒性的分子机制 在CEC中的作用还没有完全阐明。我们最近注意到A，8 可能通过激活中性刺激CECs神经酰胺的合成 鞘磷脂酶(NSMase)。神经酰胺，一种促凋亡的脂质介体，也是 对CECs有细胞毒作用。A、B和神经酰胺的作用具有共同的细胞凋亡途径 这是由线粒体功能障碍引发的。这些发现提高了 AB-nSMase在CECs中引起细胞毒性的可能性 激活-神经酰胺合成增加-线粒体功能障碍-CEC 细胞凋亡。这个项目的目标是检验中心假说 AB对CECs的细胞毒作用至少部分是由神经酰胺介导的 NSMase激活和随后因以下原因而启动的凋亡过程 线粒体功能障碍。这个项目的最终目标是开发 延缓淀粉样蛋白所致脑血管变性的治疗策略 阻断AB-神经酰胺级联反应及下游细胞凋亡过程 起源于线粒体。

DESCRIPTION(Adapted from the Investigator's Abstract): The most significant stroke risk factor is age. Age is also the most significant risk factor for Alzheimer's disease (AD). Amyloid deposition in the brain parenchyma and cerebral vasculature occurs in normal aging and in particular in AD. Amyloid deposition in the cerebral vasculature is a major cause of hemorrhagic and ischemic strokes in the elderly with or without AD. The major component of amyloid deposits in the cerebral vasculature is a small peptide, amyloid B (A,B). AB is cytotoxic to cerebral endothelial cells (CECs) in culture and in vivo. This effect of A,8 may contribute to the age-dependent development of cerebral amyloid angiopathy (CAA). The molecular mechanisms of AB cytotoxicity in CECs have not been fully elucidated. We have recently noted that A,8 stimulates ceramide synthesis in CECs probably by activating neutral sphingomyelinase (nSMase). Ceramide, a pro-apoptotic lipid mediator, is also cytotoxic to CECs. A,B and ceramide actions share certain apoptotic pathways that are triggered by mitochondrial dysfunction. These findings raise the possibility of the following cascade in AB cytotoxicity in CECs: AB - nSMase activation- increased ceramide synthesis - mitochondrial dysfunction - CEC apoptosis. The objectives of this project are to test the central hypothesis that AB cytotoxicity in CECs is at least partly mediated by ceramide following nSMase activation and the subsequent initiation of apoptotic processes due to mitochondrial dysfunction. The ultimate goal of this project is to develop therapeutic strategies to delay amyloid induced cerebrovascular degeneration by blocking the AB-ceramide cascade and the downstream apoptotic processes originating from mitochondria.