Department of Neuroscience, Genentech Inc., South San Francisco, California 94080, USA.
Cold Spring Harb Perspect Biol. 2012 May 1;4(5):a005777. doi: 10.1101/cshperspect.a005777.
Alzheimer's disease (AD) is a major cause of dementia in the elderly. Pathologically, AD is characterized by the accumulation of insoluble aggregates of Aβ-peptides that are proteolytic cleavage products of the amyloid-β precursor protein ("plaques") and by insoluble filaments composed of hyperphosphorylated tau protein ("tangles"). Familial forms of AD often display increased production of Aβ peptides and/or altered activity of presenilins, the catalytic subunits of γ-secretase that produce Aβ peptides. Although the pathogenesis of AD remains unclear, recent studies have highlighted two major themes that are likely important. First, oligomeric Aβ species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side. Second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. The mechanisms underlying these processes are beginning to be elucidated, and, although their relevance to AD remains debated, understanding these processes will likely allow new therapeutic avenues to AD.
阿尔茨海默病（AD）是老年人痴呆的主要原因。从病理学上讲，AD 的特征是不溶性 Aβ-肽聚集体的积累，Aβ-肽是淀粉样前体蛋白的蛋白水解裂解产物（“斑块”），以及由过度磷酸化的 tau 蛋白组成的不溶性细丝（“缠结”）。家族性 AD 常表现为 Aβ 肽的产生增加和/或早老素（γ-分泌酶的催化亚基）活性改变，早老素产生 Aβ 肽。尽管 AD 的发病机制仍不清楚，但最近的研究强调了两个可能很重要的主要主题。首先，寡聚 Aβ 物种对突触功能和结构具有很强的有害影响，特别是在后突触侧。其次，早老素功能的降低会损害突触传递并促进神经退行性变。这些过程的机制开始被阐明，尽管它们与 AD 的相关性仍存在争议，但了解这些过程可能会为 AD 提供新的治疗途径。
