Amyloid-β peptide (Aβ) forms metastable oligomers >50 kDa, termed AβOs, that are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aβ accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AβO formation and the high endo-lysosomal Aβ concentration together enable extensive AβO formation of Aβ42 under physiological conditions. Exploiting the enhanced AβO formation of the dimeric Aβ variant dimAβ we furthermore demonstrate targeting of AβOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AβOs.

淀粉样蛋白 β 肽 (Aβ) 形成大于 50 kDa 的亚稳态寡聚体，称为 AβO，在触发阿尔茨海默病相关过程（如突触功能障碍和 Tau 病理学，包括 Tau 错误定位）方面比 Aβ 淀粉样原纤维更有效。在神经元中，Aβ 在低 pH 值下在溶酶体囊泡中积累。在这里，我们表明，当 pH 从细胞外 pH 降低到溶酶体内 pH 值时，AβO 组装速度加快了 8,000 倍，但以淀粉样原纤维的形成为代价。pH 诱导的 AβO 形成促进和高内溶酶体 Aβ 浓度共同使 Aβ42 在生理条件下广泛形成 AβO。利用二聚体 Aβ 变体 dimAβ 增强的 AβO 形成，我们进一步证明了 AβO 靶向树突棘，有效诱导 Tau 错配，这是 tauopathies 的关键因素，和神经元活动受损。结果表明，内体/溶酶体系统是组装病理机械相关 AβO 的主要位点。