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.

中文翻译：

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25 岁时阿尔茨海默病的淀粉样蛋白假说。


尽管关于 β 淀粉样蛋白（或 Aβ 假说）的争论仍在继续，但来自世界各地实验室和诊所的新证据支持这样的概念：Aβ42 和相关 Aβ 肽的产生和清除之间的不平衡是阿尔茨海默氏病的一个非常早期且经常引发的因素。 (AD) 确认早老素是 γ-分泌酶的催化位点提供了一个关键：导致早发 AD 的所有显性突变都发生在反应的底物（淀粉样前体蛋白，APP）或蛋白酶（早老素）中。唐氏综合症中野生型 APP 基因的复制导致青少年出现 Aβ 沉积，随后出现 AD 载脂蛋白 E4 典型的小胶质细胞增多症、星形细胞增多症和神经原纤维缠结，这在 > 40% 的病例中易患 AD。研究发现，从 AD 患者大脑中分离出的可溶性 Aβ42 寡聚体可以减少啮齿动物海马的突触数量、抑制长时程增强并增强长期突触抑制，将其注射到健康大鼠体内会损害记忆力。 。人类寡聚物还会诱导 AD 相关表位处 tau 蛋白的过度磷酸化，并导致培养的神经元出现神经炎性营养不良。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 (CSF) Aβ42 和淀粉样蛋白 PET 阳性早于其他 AD 表现很多年。最重要的是，最近对三种不同 Aβ 抗体（solanezumab、crenezumab 和 aducanumab）的试验表明，对轻度 AD 受试者的事后分析显示认知能力下降速度减缓。 尽管 AD 发病机制有很多因素，但 Aβ 稳态失调已成为最广泛验证和引人注目的治疗靶点。