Microglia and the immune pathology of Alzheimer disease
Microglia and the immune pathology of Alzheimer disease
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DOI：
10.1086/302477
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发表时间：
1999-07-01
影响因子：
9.8
通讯作者：
Giulian, D
中科院分区：
文献类型：
--
作者：
Giulian, D
阿尔茨海默病（AD）是一种慢性大脑退行性疾病，是老年人最常见的痴呆症。在过去的十年中，许多努力已经投入到描述这种疾病的机制和寻找新的治疗策略。阿尔茨海默病的组织病理学已经确定，其特征包括老年斑（含有b-淀粉样肽的复杂蛋白聚集体[Ab]）、神经缠结（含有过度磷酸化的t蛋白的神经元残留物）、神经元丢失、突触连接受损和反应性胶质增生。反应性胶质瘤既包括攻击老年斑的小胶质细胞（图1），也包括围绕斑块复合体作为保护膜的星形胶质细胞。关于痴呆症发病机制的观点在过去几年中发生了重大变化。人们普遍认为，Ab代谢异常对AD的发展至关重要（Selkoe 1993）。流行病学和生物化学研究已经确定ab前体蛋白（APP）的突变是家族性AD的致病因素，而载脂蛋白E （apo E）的同型型已被确定为散发疾病的危险因素（Selkoe 1993； Strittmatter等人1993；Price等人1998；Growdon 1999）。此外，由于早老素异常似乎会影响APP的加工和Ab的产生，因此痴呆症的细胞内方面也受到了很多关注（Kovacs and Tanzi 1998; Sisodia et al. 1999 [in this issue]）。无论疾病的起始事件是什么，人们都认为神经元和突触损伤是AD患者认知功能丧失的原因。仍不确定的是将Ab代谢与神经元丧失联系起来的事件。已经提出了许多导致AD病理的疾病途径；这里考虑的是大脑免疫细胞小胶质细胞的作用。
Alzheimer disease (AD) is a chronic degenerative disorder of the brain, which accounts for the most common form of dementia in the elderly. During the past decade, much effort has been devoted to the delineation of mechanisms of this disease and to the search for new treatment strategies. The histopathology of AD is well established, with hallmarks including senile plaque (complex protein aggregates containing the b-amyloid peptide [Ab]), neuritic tangles (remnants of neurons containing hyperphosphorylated t protein), loss of neurons, damaged synaptic connections, and reactive gliosis. Reactive gliosis involves both microglia, which attack the senile plaque (fig. 1), and astroglia, which surround the plaque complex as a protective wrap. Views concerning the pathogenesis of dementia have evolved significantly during the past few years. It is generally agreed that abnormalities of Ab metabolism are critical for the development of AD (Selkoe 1993). Epidemiology, coupled with biochemical studies, has identified mutations within Ab-precursor protein (APP) as causal factors for familial forms of AD, whereas isoforms of apolipoprotein E (apo E) have been identified as risk factors for sporadic disease (Selkoe 1993; Strittmatter et al. 1993; Price et al. 1998; Growdon 1999). Moreover, intracellular aspects of dementia have received much attention, since abnormalities in presenilin appear to affect processing of APP and production of Ab (Kovacs and Tanzi 1998; Sisodia et al. 1999 [in this issue]). Regardless of initiating events for the disease, it is recognized that neuronal and synaptic damages are responsible for loss of cognitive function in AD. What remain uncertain are the events that link Ab metabolism with loss of neurons. Many disease pathways contributing to AD pathology have been proposed; the role of the brain immune cell, the microglia, is considered here.