Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Trends Neurosci. 2019 May;42(5):310-322. doi: 10.1016/j.tins.2019.03.003.
Evidence suggests that amyloid β is highly toxic to synapses in a phospho-Tau-dependent manner. Here, I present a hypothesis that links previous evidence from the first rise of amyloid β through to Tau tangles and neurodegeneration. In the immediate vicinity of plaques, concentrated soluble amyloid β occurs in equilibrium with deposited forms. Initially, plaques cover only a small percentage of brain volume. Microglia, by efficiently removing damaged synapses, may prevent spread of damage along the axon, restricting damage to the immediate vicinity of plaques. However, as plaque load increases, as seen in Alzheimer's disease, an individual axon may suffer multiple points of damage, leading to dissociation of Tau, formation of a tangle, and loss of the axon. As more axons suffer this fate, the network eventually degenerates. According to this hypothesis, the degree of plaque load that an individual can tolerate would depend on the efficiency of their microglia in removing amyloid-β-damaged synapses and the distribution of plaques, relative to axon trajectories, would determine the eventual cognitive symptoms.
有证据表明，淀粉样蛋白β以磷酸化 Tau 依赖的方式对突触具有高度毒性。在这里，我提出了一个假设，将淀粉样蛋白β最初升高的先前证据与 Tau 缠结和神经退行性变联系起来。在斑块的紧邻区域，浓缩的可溶性淀粉样蛋白β与沉积形式处于平衡状态。最初，斑块只覆盖大脑体积的一小部分。小胶质细胞通过有效清除受损的突触，可以防止损伤沿着轴突传播，从而将损伤限制在斑块的紧邻区域。然而，随着斑块负荷的增加，如在阿尔茨海默病中所见，单个轴突可能会遭受多个损伤点，导致 Tau 分离、缠结形成和轴突丢失。随着更多的轴突遭受这种命运，网络最终会退化。根据这个假设，个体能够承受的斑块负荷程度将取决于其小胶质细胞清除淀粉样蛋白β损伤突触的效率，以及斑块的分布相对于轴突轨迹，将决定最终的认知症状。
