AMYLOID INDUCED CEREBROENDOTHELIAL DEGENERATION

描述（改编自研究者摘要）：最重要的 中风风险因素是年龄。年龄也是最重要的风险因素， 阿尔茨海默病（AD）。脑实质中淀粉样沉积， 脑血管系统发生在正常衰老中，特别是在AD中。淀粉样 脑血管系统中的沉积是出血和 有或无AD的老年人缺血性中风。的主要组分 淀粉样蛋白沉积在脑血管中是一种小肽，淀粉样蛋白B （A，B）。AB对培养的脑内皮细胞（CEC）具有细胞毒性， vivo. A8的这种作用可能有助于年龄依赖性的发育， 脑淀粉样血管病（CAA）。AB细胞毒作用的分子机制 在CEC中尚未完全阐明。我们最近注意到， 刺激CEC神经酰胺合成可能是通过激活中性 鞘磷脂酶（nSMase）。神经酰胺是一种促凋亡脂质介质， 对CEC有细胞毒性。A、B和神经酰胺作用共享某些凋亡途径 是由线粒体功能障碍引发的这些发现提高了 CEC中AB细胞毒性中以下级联反应的可能性：AB-nSM酶 激活-神经酰胺合成增加-线粒体功能障碍- CEC 凋亡这个项目的目标是检验中心假设 CEC中的AB细胞毒性至少部分由神经酰胺介导， nSMase激活和随后的凋亡过程的启动， 线粒体功能障碍该项目的最终目标是开发 延缓淀粉样蛋白诱导的脑血管变性的治疗策略 阻断AB-神经酰胺级联和下游凋亡过程 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.