β淀粉样肽在阿尔茨海默症发病中的分子机制

Progress in Molecular Mechanisms of β-amyloid Peptides in Alzheimer's Disease

作为老年性痴呆的主要类型,阿尔茨海默症(AD)的病理特征包括大脑局部,尤其是海马和皮层神经元退行性变化,细胞内神经原纤维缠结和细胞外老年斑沉淀,其中老年斑的主要毒性成分为β-淀粉样肽(Aβ).随着对AD研究的深入,关于疾病发生的Aβ假说得到了深入的发展,越来越多的证据显示Aβ可能是AD发生的原发性病理因子.Aβ假说认为,AD是一种由于基因缺陷直接或间接改变淀粉样前蛋白(APP)表达或蛋白酶解过程,从而影响Aβ聚集稳定性的病理综合征,Aβ产生和清除之间的平衡逐渐改变,聚集态的Aβ累积引发连串的复杂反应,包括突触/突起的变化,Tau蛋白磷酸化,递质丢失,神经胶质增生和炎症反应等,最终出现神经元功能失调,死亡,斑块形成,神经原纤维缠积等病理现象.但Aβ究竟是通过什么样的分子途径引发AD的,Aβ作用的部位在哪里,Aβ毒性与其聚集状态的关系等等问题都还未能完全揭示.结合近年来实验室的研究结果和体会,综述了Aβ最新的研究进展.

The pathological presentation of Alzheimer disease （AD）, the leading cause of senile dementia, involves regionalized neuronal death and an accumulation of intraneuronal and extracellular filaments termed neurofibrillary tangles and senile plaques, respectively. One of the β-amyloid peptides （Aβ）, the Aβ1-42 form, is primarily responsible for neuronal damage and cell death that is the main component in the senile plaques, Over the past twenty years, the amyloid hypothesis has been strongly supported by a wealth of evidence, including data from genetic studies of Alzheimer disease. Amyloid cascade hypothesis states that the accumulation and deposition of fibrillar Aβ is the primary driver of neurodegeneration and cognitive decline leading to dementia. AD is a clinicopathological syndrome in which different gene defects can lead directly or indirectly to alter APP expression or proteolytic processing as such to change Aβ stability or aggregation. These result in a chronic imbalance between Aβ production and clearance. Gradual accumulation of aggregated Aβ initiates a complex, multistep cascade that includes gliosis, inflammatory changes, neuritic/synaptic change, tangles and transmitter loss. The evidence that links Aβ to the pathogenesis of AD is substantial, but the means by which these peptides exert their toxic effects, and where in neuronal cells they act, is far from clear. The up-to-date proceeding in the molecular mechanism of β-amyloid peptides is overviewed.