Kurz Carolin, Walker Lauren, Rauchmann Boris-Stephan, Perneczky Robert
Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
Translational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
Neuropathol Appl Neurobiol. 2022 Apr;48(3):e12782. doi: 10.1111/nan.12782. Epub 2022 Feb 2.
The pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis in Alzheimer's disease (AD) and their relation to vascular disease and immunological changes are yet to be fully explored. Amyloid-β (Aβ) aggregation, vascular damage and altered immune response interact at the blood-brain barrier (BBB), affecting the brain endothelium and fuelling neurodegeneration. The aim of the present systematic literature review was to critically appraise and to summarise the published evidence on the clinical correlations and pathophysiological concepts of BBB damage in AD, focusing on human data. The PubMed, Cochrane, Medline and Embase databases were searched for original research articles, systematic reviews and meta-analyses, published in English language from 01/2000 to 07/2021, using the keywords Alzheimer*, amyloid-β or β-amyloid or abeta and BBB. This review shows that specific changes of intercellular structures, reduced expression of transendothelial carriers, induction of vasoactive mediators and activation of both astroglia and monocytes/macrophages characterise BBB damage in human AD and AD models. BBB dysfunction on magnetic resonance imaging takes place early in the disease course in AD-specific brain regions. The toxic effects of Aβ and apolipoprotein E (ApoE) are likely to induce a non-cerebral-amyloid-angiopathy-related degeneration of endothelial cells, independently of cerebrovascular disease; however, some of the observed structural changes may just arise with age. Small vessel disease, ApoE, loss of pericytes, proinflammatory signalling and cerebral amyloid angiopathy enhance BBB damage. Novel therapeutic approaches for AD, including magnetic resonance-guided focused ultrasound, aim to open the BBB, potentially leading to an improved drainage of Aβ along perivascular channels and increased elimination from the brain. In vitro treatments with ApoE-modifying agents yielded promising effects on modulating BBB function. Reducing cardiovascular risk factors represents one of the most promising interventions for dementia prevention at present. However, further research is needed to elucidate the connection of BBB damage and tau pathology, the role of proinflammatory mediators in draining macromolecules and cells from the cerebral parenchyma, including their contribution to cerebral amyloid angiopathy. Improved insight into these pathomechanisms may allow to shed light on the role of Aβ deposition as a primary versus a secondary event in the complex pathogenesis of AD.
导致阿尔茨海默病（AD）中突触丧失、神经元丧失、脑萎缩和胶质增生的病理过程及其与血管疾病和免疫变化的关系尚未得到充分探索。淀粉样β蛋白（Aβ）聚集、血管损伤和免疫反应改变在血脑屏障（BBB）处相互作用，影响脑内皮细胞并加剧神经退行性变。本系统文献综述的目的是严格评估和总结已发表的关于AD中血脑屏障损伤的临床相关性和病理生理概念的证据，重点关注人类数据。在PubMed、Cochrane、Medline和Embase数据库中检索了2000年1月至2021年7月以英文发表的原创研究文章、系统评价和荟萃分析，使用的关键词为阿尔茨海默*、淀粉样β蛋白或β - 淀粉样蛋白或阿贝他和血脑屏障。本综述表明，细胞间结构的特定变化、跨内皮载体表达降低、血管活性介质的诱导以及星形胶质细胞和单核细胞/巨噬细胞的激活是人类AD和AD模型中血脑屏障损伤的特征。磁共振成像上的血脑屏障功能障碍在AD特定脑区的疾病进程早期就会出现。Aβ和载脂蛋白E（ApoE）的毒性作用可能会诱导内皮细胞发生与非脑淀粉样血管病相关的变性，与脑血管疾病无关；然而，一些观察到的结构变化可能仅仅是随着年龄增长而出现的。小血管疾病、ApoE、周细胞丧失、促炎信号传导和脑淀粉样血管病会加剧血脑屏障损伤。AD的新型治疗方法，包括磁共振引导聚焦超声，旨在打开血脑屏障，可能会改善Aβ沿血管周围通道的引流并增加其从脑中的清除。用ApoE修饰剂进行的体外治疗在调节血脑屏障功能方面产生了有前景的效果。降低心血管危险因素是目前预防痴呆最有前景的干预措施之一。然而，需要进一步研究来阐明血脑屏障损伤与tau病理的联系、促炎介质在从脑实质排出大分子和细胞中的作用，包括它们对脑淀粉样血管病的贡献。对这些病理机制的深入了解可能有助于阐明Aβ沉积在AD复杂发病机制中作为原发性事件与继发性事件的作用。
