The amyloid hypothesis of Alzheimer's disease at 25 years.
The amyloid hypothesis of Alzheimer's disease at 25 years.
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DOI：
10.15252/emmm.201606210
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发表时间：
2016-06
影响因子：
11.1
通讯作者：
Hardy J
中科院分区：
文献类型：
--
作者：
Selkoe DJ;Hardy J
尽管关于淀粉样蛋白-β(或A-β假说)的争论仍在继续，但来自世界各地的实验室和临床的新证据支持这一概念，即Aβ42和相关Aβ多肽的产生和清除之间的失衡是阿尔茨海默病(AD)的一个非常早期的、通常是启动因素。早老素是γ分泌酶的催化位点的确认提供了一个关键：所有导致早发性AD的显性突变要么发生在底物(淀粉样前体蛋白，APP)中，要么发生在产生Aβ的反应的蛋白酶(早老素)中。唐氏症患者野生型APP基因的重复导致青少年Aβ沉积，随后是AD典型的小胶质细胞增多症、星形细胞增多症和神经纤维缠结。载脂蛋白E4在40%的病例中易患AD，已发现会损害Aβ从大脑中的清除。从AD患者脑组织中分离到的A-β-42的可溶性寡聚体可以减少大鼠海马区突触数目，抑制长时程增强，增强长时程突触抑制，并将其注射到健康大鼠体内会损害记忆。人类寡聚体还诱导AD相关表位tau的过度磷酸化，并在培养的神经元中引起神经性营养不良。将人APP与人tau转基因小鼠杂交可增强tau阳性神经毒性。在人类中，新的研究表明，低脑脊液Aβ42和淀粉样PET阳性比其他AD表现早许多年。最重要的是，最近对三种不同的Aβ抗体(Solane zumab、crenezumab和aducanumab)的试验表明，在对轻度AD受试者的专项分析中，认知能力下降的速度有所放缓。尽管许多因素参与了AD的发病机制，但β代谢紊乱已成为最广泛验证和最引人注目的治疗靶点。
Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.