Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Neurodegener Dis. 2012;10(1-4):324-8. doi: 10.1159/000332821. Epub 2011 Dec 7.
The vascular deposition of amyloid known as cerebral amyloid angiopathy (CAA)--an age-associated condition and a common finding in Alzheimer's disease--compromises cerebral blood flow, causing macro/microhemorrhages and/or cognitive impairment. Very little is known about the mechanisms causing CAA-related degeneration of cerebral vascular cells. The Dutch E22Q familial amyloid-β (Aβ) variant is primarily associated with CAA, and manifests clinically with severe cerebral hemorrhages.
We aimed to determine the molecular mechanisms causing apoptosis of cerebral endothelial cells in the presence of wild-type Aβ40 or its vasculotropic E22Q variant.
We challenged human brain microvascular endothelial cells with both Aβ variants, and studied the apoptotic pathways triggered by these peptides.
Caspase-mediated apoptotic pathways were elicited by both peptides within time frames correlating with their aggregation properties and formation of oligomeric/protofibrillar assemblies. Our data revealed a primary activation of caspase-8 (typically triggered by death receptors) with secondary engagement of caspase-9, with cytochrome C and apoptosis-inducing factor release from the mitochondria, suggesting the independent or synergistic engagement of extrinsic and intrinsic apoptotic mechanisms.
Our data demonstrate the induction of caspase-8- and caspase-9-dependent mitochondrial-mediated apoptotic pathways by Aβ oligomers/protofibrils in vascular cells, likely implicating a primary activation of death receptors.
已知血管沉积淀粉样蛋白（CAA）——一种与年龄相关的疾病，也是阿尔茨海默病的常见发现——会损害脑血流，导致大/微出血和/或认知障碍。目前对于导致与 CAA 相关的脑血管细胞退化的机制知之甚少。荷兰 E22Q 家族性淀粉样蛋白-β（Aβ）变体主要与 CAA 相关，并表现为严重的脑出血。
我们旨在确定在存在野生型 Aβ40 或其血管致病 E22Q 变体的情况下，导致脑内皮细胞凋亡的分子机制。
我们用两种 Aβ 变体挑战人脑微血管内皮细胞，并研究这些肽引发的凋亡途径。
这两种肽都在与其聚集特性和寡聚体/原纤维形成相关的时间框架内引发了半胱天冬酶介导的凋亡途径。我们的数据显示，caspase-8（通常由死亡受体触发）被主要激活，随后 caspase-9 被激活，细胞色素 C 和凋亡诱导因子从线粒体释放，这表明外源性和内源性凋亡机制的独立或协同参与。
我们的数据表明 Aβ 寡聚体/原纤维在血管细胞中诱导 caspase-8 和 caspase-9 依赖性线粒体介导的凋亡途径，可能涉及死亡受体的早期激活。
