Parodi-Rullán Rebecca, Sone Je Yeong, Fossati Silvia
Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Department of Psychiatry, Center for Brain Health, NYU School of Medicine, New York, NY, USA.
J Alzheimers Dis. 2019;72(4):1019-1039. doi: 10.3233/JAD-190357.
Alzheimer's disease (AD) is the most prevalent form of dementia. Cerebrovascular dysfunction is one of the earliest events in the pathogenesis of AD, as well as in vascular and mixed dementias. Cerebral amyloid angiopathy (CAA), the deposition of amyloid around cerebral vessels, is observed in up to 90% of AD patients and in approximately 50% of elderly individuals over 80 years of age. CAA is a strong contributor to vascular dysfunction in AD. CAA-laden brain vessels are characterized by dysfunctional hemodynamics and leaky blood-brain barrier (BBB), contributing to clearance failure and further accumulation of amyloid-β (Aβ) in the cerebrovasculature and brain parenchyma. Mitochondrial dysfunction is increasingly recognized as an important early initiator of the pathogenesis of AD and CAA. The objective of this review is to discuss the effects of Aβ on cerebral microvascular cell function, focusing on its impact on endothelial mitochondria. After introducing CAA and its etiology and genetic risk factors, we describe the pathological relationship between cerebrovascular amyloidosis and brain microvascular endothelial cell dysfunction, critically analyzing its roles in disease progression, hypoperfusion, and BBB integrity. Then, we focus on discussing the effect of Aβ challenge on endothelial mitochondrial dysfunction pathways, and their contribution to the progression of neurovascular dysfunction in AD and dementia. Finally, we report potential pharmacological and non-pharmacological mitochondria-targeted therapeutic strategies which may help prevent or delay cerebrovascular failure.
阿尔茨海默病（AD）是最常见的痴呆形式。脑血管功能障碍是AD发病机制中最早出现的事件之一，在血管性痴呆和混合性痴呆中也是如此。脑淀粉样血管病（CAA），即脑血管周围淀粉样蛋白的沉积，在高达90%的AD患者以及约50%的80岁以上老年人中可见。CAA是AD血管功能障碍的一个重要促成因素。载有CAA的脑血管具有血流动力学功能障碍和血脑屏障（BBB）渗漏的特征，导致清除失败以及淀粉样β蛋白（Aβ）在脑血管系统和脑实质中进一步积聚。线粒体功能障碍越来越被认为是AD和CAA发病机制的重要早期启动因素。本综述的目的是讨论Aβ对脑微血管细胞功能的影响，重点关注其对内皮线粒体的影响。在介绍CAA及其病因和遗传风险因素后，我们描述脑血管淀粉样变性与脑微血管内皮细胞功能障碍之间的病理关系，批判性地分析其在疾病进展、灌注不足和BBB完整性中的作用。然后，我们重点讨论Aβ刺激对内皮线粒体功能障碍途径的影响，以及它们对AD和痴呆中神经血管功能障碍进展的作用。最后，我们报告了可能有助于预防或延缓脑血管功能衰竭的潜在药理学和非药理学线粒体靶向治疗策略。
