Amyloidosis associated with cerebral amyloid angiopathy: cell signaling pathways elicited in cerebral endothelial cells.
Amyloidosis associated with cerebral amyloid angiopathy: cell signaling pathways elicited in cerebral endothelial cells.
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DOI：
10.3233/jad-140027
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Rostagno A
中科院分区：
文献类型：
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作者：
Ghiso J;Fossati S;Rostagno A
大量遗传、生化和体内数据表明，β 淀粉样蛋白 (Aβ) 的逐渐积累在阿尔茨海默病 (AD) 的发病机制中发挥着核心作用。历史上以脑实质斑块的重要性为中心，脑淀粉样血管病 (CAA)——一种经常被忽视的淀粉样沉积物，存在于 >80% 的 AD 病例中——在疾病发病机制中的作用现在开始显现。 CAA始终与微血管改变、缺血性病变、微出血和大出血以及痴呆相关，逐渐影响脑血流，改变血脑屏障通透性，干扰大脑清除机制，并引发一系列有害的促炎和代谢事件，从而损害神经血管单元的完整性。新证据强调了前原纤维 Aβ 在诱导脑内皮细胞功能障碍中的作用。最近发现的寡聚 Aβ 物种与 TRAIL DR4 和 DR5 细胞表面死亡受体的相互作用介导线粒体途径的参与和多个 caspase 的连续激活，引发一系列细胞死亡机制，同时为探索基于机制的治疗干预措施以保持神经血管单元的完整性提供了机会。
Substantial genetic, biochemical, and in vivo data indicate that progressive accumulation of amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease (AD). Historically centered in the importance of parenchymal plaques, the role of cerebral amyloid angiopathy (CAA)—a frequently neglected amyloid deposit present in >80% of AD cases—for the mechanism of disease pathogenesis is now starting to emerge. CAA consistently associates with microvascular modifications, ischemic lesions, micro- and macro-hemorrhages, and dementia, progressively affecting cerebral blood flow, altering blood-brain barrier permeability, interfering with brain clearance mechanisms and triggering a cascade of deleterious pro-inflammatory and metabolic events that compromise the integrity of the neurovascular unit. New evidence highlights the contribution of pre-fibrillar Aβ in the induction of cerebral endothelial cell dysfunction. The recently discovered interaction of oligomeric Aβ species with TRAIL DR4 and DR5 cell surface death receptors mediates the engagement of mitochondrial pathways and sequential activation of multiple caspases, eliciting a cascade of cell death mechanisms while unveiling an opportunity for exploring mechanistic-based therapeutic interventions to preserve the integrity of the neurovascular unit.