Martinez Bridget, Peplow Philip V
Department of Molecular & Cellular Biology, University of California, Merced, Merced, CA, USA; Department of Medicine, St. Georges University School of Medicine, Grenada; Department of Physics and Engineering, Los Alamos National Laboratory, Los Alamos, NM, USA.
Department of Anatomy, University of Otago, Dunedin, New Zealand.
Neural Regen Res. 2019 Jul;14(7):1158-1176. doi: 10.4103/1673-5374.251192.
The most common age-related neurodegenerative disease is Alzheimer's disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation.
最常见的与年龄相关的神经退行性疾病是阿尔茨海默病（AD），其特征是细胞外斑块中存在聚集的淀粉样β（Aβ）肽，神经元内神经原纤维缠结中存在聚集的高度磷酸化tau蛋白，同时伴有胆碱能神经元丧失、突触改变以及脑内慢性炎症。这些导致认知功能逐渐受损。有证据表明AD中存在先天性免疫激活伴小胶质细胞增生。经典激活的小胶质细胞（M1状态）分泌炎症和神经毒性介质，外周免疫细胞被招募到脑内的炎症部位。美国食品药品监督管理局（FDA）批准的用于治疗AD的少数药物可改善症状，但不会改变疾病进展过程，且可能会引起一些不良影响。在AD动物模型试验中针对Aβ的主动和被动免疫疗法的转化在临床试验中取得的成功有限。在疾病过程早期用免疫调节/抗炎药物进行治疗，虽然不能预防，但能够抑制Aβ和tau聚集的炎症后果。本综述中描述的研究已经确定了几种具有免疫调节特性的药物，它们在AD动物模型中减轻了AD病理和认知障碍。所综述的大多数动物研究使用的是早发性AD的转基因模型。需要更加努力地创建晚发性AD模型。在老年AD动物模型中，涉及两种或更多种受试药物的联合疗法，或其中一种药物与一种基于细胞的疗法联合使用的效果，值得研究。
