Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Laboratoire de Neuropathologie Raymond-Escourolle, Hopital de la Pitie-Salpetriere, 47, boulevard de l'Hopital, 75651, Paris Cedex 13, France.
Acta Neuropathol. 2016 Jan;131(1):5-25. doi: 10.1007/s00401-015-1516-y. Epub 2015 Dec 29.
In brains of patients with Alzheimer's disease (AD), Aβ peptides accumulate in parenchyma and, almost invariably, also in the vascular walls. Although Aβ aggregation is, by definition, present in AD, its impact is only incompletely understood. It occurs in a stereotypical spatiotemporal distribution within neuronal networks in the course of the disease. This suggests a role for synaptic connections in propagating Aβ pathology, and possibly of axonal transport in an antero- or retrograde way-although, there is also evidence for passive, extracellular diffusion. Striking, in AD, is the conjunction of tau and Aβ pathology. Tau pathology in the cell body of neurons precedes Aβ deposition in their synaptic endings in several circuits such as the entorhino-dentate, cortico-striatal or subiculo-mammillary connections. However, genetic evidence suggests that Aβ accumulation is the first step in AD pathogenesis. To model the complexity and consequences of Aβ aggregation in vivo, various transgenic (tg) rodents have been generated. In rodents tg for the human Aβ precursor protein, focal injections of preformed Aβ aggregates can induce Aβ deposits in the vicinity of the injection site, and over time in more distant regions of the brain. This suggests that Aβ shares with α-synuclein, tau and other proteins the property to misfold and aggregate homotypic molecules. We propose to group those proteins under the term "propagons". Propagons may lack the infectivity of prions. We review findings from neuropathological examinations of human brains in different stages of AD and from studies in rodent models of Aβ aggregation and discuss putative mechanisms underlying the initiation and spread of Aβ pathology.
在阿尔茨海默病（AD）患者的大脑中，Aβ 肽在实质中积累，几乎无一例外地也在血管壁中积累。虽然 Aβ 聚集是 AD 的定义特征，但它的影响还不完全清楚。它在疾病过程中沿着神经元网络的典型时空分布发生。这表明突触连接在传播 Aβ 病理学方面发挥作用，并且可能通过轴突运输以顺行或逆行方式发生-尽管也有证据表明存在被动的细胞外扩散。AD 中引人注目的是tau 和 Aβ 病理学的结合。在几个回路中，神经元细胞体中的 tau 病理学先于其突触末梢中的 Aβ 沉积，例如内嗅齿状回、皮质纹状体或下丘乳突连接。然而，遗传证据表明 Aβ 积累是 AD 发病机制的第一步。为了在体内模拟 Aβ 聚集的复杂性和后果，已经生成了各种转基因（tg）啮齿动物。在人类 Aβ 前体蛋白转基因的啮齿动物中，预先形成的 Aβ 聚集体的局灶性注射可以在注射部位附近诱导 Aβ 沉积，并随着时间的推移在大脑的更远区域诱导沉积。这表明 Aβ 与 α-突触核蛋白、tau 和其他蛋白质一样具有错误折叠和聚集同源分子的特性。我们建议将这些蛋白质归为“传播子”一词。传播子可能缺乏朊病毒的感染性。我们回顾了 AD 不同阶段人类大脑的神经病理学检查结果以及 Aβ 聚集的啮齿动物模型研究结果，并讨论了 Aβ 病理学起始和传播的潜在机制。
