Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease.
Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease.
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发表时间：
2002
影响因子：
21.1
通讯作者：
Y. Suh;F. Checler
中科院分区：
文献类型：
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作者：
Y. Suh;F. Checler
阿尔茨海默病(AD)是最常见的痴呆病因，其神经病理背景是由淀粉样前体蛋白(APP)和富含tau的神经原纤维缠结产生的含有β-淀粉样蛋白(Aβ)的淀粉样斑块。到目前为止，家族性和散发性AD的病因和进展还没有完全阐明。早发性阿尔茨海默病的常染色体显性遗传形式是由编码APP、早老素-1(14号染色体)和早老素-2(1号染色体)的基因突变引起的。APP被几种不同的酶，如分泌酶和/或半胱氨酸酶处理，产生Aβ和羧基末端片段，这与阿尔茨海默病的发病机制有关。阿尔茨海默病和帕金森病分别与大脑中Aβ和α-突触核蛋白的积累有关。一些患者同时具有这两种疾病的临床和病理特征，增加了发病途径重叠的可能性。最近的研究有力地提示了Aβ、早老素和/或α-突触核蛋白之间可能的致病相互作用。因此，阻止Aβ和α-突触核蛋白积累的治疗可能会使广泛的神经退行性疾病受益。本文就APP的转运和加工、AD发病机制中的淀粉样级联假说、早老素的生理和病理作用、α-突触核蛋白的分子特征、它们之间的相互作用以及AD的治疗策略作一综述。
Alzheimer's disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing beta-amyloid (A beta) derived from amyloid precursor protein (APP) and tau-rich neurofibrillary tangles. To date, the cause and progression of both familial and sporadic AD have not been fully elucidated. The autosomal-dominant inherited forms of early-onset Alzheimer's disease are caused by mutations in the genes encoding APP, presenilin-1 (chromosome 14), and presenilin-2 (chromosome 1). APP is processed by several different proteases such as secretases and/or caspases to yield A beta and carboxyl-terminal fragments, which have been implicated in the pathogenesis of Alzheimer's disease. Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of A beta and alpha-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenic pathways. Recent studies have strongly suggested the possible pathogenic interactions between A beta, presenilins, and/or alpha-synuclein. Therefore, treatments that block the accumulation of A beta and alpha-synuclein might benefit a broad spectrum of neurodegenerative disorders. This review covers the trafficking and processing of APP, amyloid cascade hypothesis in AD pathogenesis, physiological and pathological roles of presenilins, molecular characteristics of alpha-synuclein, their interactions, and therapeutic strategies for AD.