Differential activation of mitochondrial apoptotic pathways by vasculotropic amyloid-β variants in cells composing the cerebral vessel walls
Differential activation of mitochondrial apoptotic pathways by vasculotropic amyloid-β variants in cells composing the cerebral vessel walls
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DOI：
10.1096/fj.09-139584
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发表时间：
2010-01-01
期刊：
影响因子：
4.8
通讯作者：
Rostagno, A.
中科院分区：
文献类型：
--
作者：
Fossati, S.;Cam, J.;Rostagno, A.
脑淀粉样血管病 (CAA) 是一种与年龄相关的疾病，是阿尔茨海默病的常见症状，其中 80% 以上的病例以淀粉样蛋白 -β (Aβ) 血管沉积为特征。在第 21-23 位发生取代的家族性 Aβ 变异主要与 CAA 相关，尽管它们表现出截然不同的临床表型：脑出血或痴呆。最近报道的皮埃蒙特 L34V A beta 突变体位于热点 21-23 之外，显示出类似的出血表型，尽管其攻击性不如广泛研究的荷兰 E22Q 突变体。我们监测了刺激具有变体和野生型 A beta 40 的非纤维结构的人脑微血管内皮和平滑肌细胞后发生的细胞凋亡事件。所有肽均引发类似的半胱天冬酶介导的线粒体途径的诱导，尽管时间范围和强度不同。激活的通路容易受到药理学调节，通过直接抑制线粒体细胞色素 c 释放或通过泛和通路特异性 caspase 抑制剂的作用，清楚地表明外在和内在机制的独立或协同作用。 Aβ 肽的结构分析表明细胞凋亡先于原纤维形成，与寡聚体和/或原原纤维的存在相关。数据支持这样的观点，即罕见的基因突变构成了理解 CAA 分子发病机制的独特范式。-Fossati, S.、Cam, J.、Meyerson, J.、Mezhericher, E.、Romero, I. A.、Couraud, P. O.、Weksler, B. B.、Ghiso, J.、Rostagno, A. 血管活性物质对线粒体凋亡途径的差异激活 构成脑血管壁的细胞中存在β淀粉样蛋白变体。 FASEB J. 24, 229-241 (2010)。 www.fasebj.org
Cerebral amyloid angiopathy (CAA) is an age-associated condition and a common finding in Alzheimer's disease in which amyloid-beta (A beta) vascular deposits are featured in > 80% of the cases. Familial A beta variants bearing substitutions at positions 21-23 are primarily associated with CAA, although they manifest with strikingly different clinical phenotypes: cerebral hemorrhage or dementia. The recently reported Piedmont L34V A beta mutant, located outside the hot spot 21-23, shows a similar hemorrhagic phenotype, albeit less aggressive than the widely studied Dutch E22Q variant. We monitored the apoptotic events occurring after stimulation of human brain microvascular endothelial and smooth muscle cells with nonfibrillar structures of both variants and wild-type A beta 40. Induction of analogous caspase-mediated mitochondrial pathways was elicited by all peptides, although within different time frames and intensity. Activated pathways were susceptible to pharmacological modulation either through direct inhibition of mitochondrial cytochrome c release or by the action of pan- and pathway-specific caspase inhibitors, giving a clear indication of the independent or synergistic engagement of both extrinsic and intrinsic mechanisms. Structural analyses of the A beta peptides showed that apoptosis preceded fibril formation, correlating with the presence of oligomers and/or protofibrils. The data support the notion that rare genetic mutations constitute unique paradigms to understand the molecular pathogenesis of CAA.-Fossati, S., Cam, J., Meyerson, J., Mezhericher, E., Romero, I. A., Couraud, P. O., Weksler, B. B., Ghiso, J., Rostagno, A. Differential activation of mitochondrial apoptotic pathways by vasculotropic amyloid-beta variants in cells composing the cerebral vessel walls. FASEB J. 24, 229-241 (2010). www.fasebj.org