The precise mechanisms that lead to cognitive decline in Alzheimer’s disease are unknown. Here we identify amyloid-plaque-associated axonal spheroids as prominent contributors to neural network dysfunction. Using intravital calcium and voltage imaging, we show that a mouse model of Alzheimer’s disease demonstrates severe disruption in long-range axonal connectivity. This disruption is caused by action-potential conduction blockades due to enlarging spheroids acting as electric current sinks in a size-dependent manner. Spheroid growth was associated with an age-dependent accumulation of large endolysosomal vesicles and was mechanistically linked with Pld3—a potential Alzheimer’s-disease-associated risk gene¹ that encodes a lysosomal protein^2,3 that is highly enriched in axonal spheroids. Neuronal overexpression of Pld3 led to endolysosomal vesicle accumulation and spheroid enlargement, which worsened axonal conduction blockades. By contrast, Pld3 deletion reduced endolysosomal vesicle and spheroid size, leading to improved electrical conduction and neural network function. Thus, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer’s disease, independent of amyloid removal.

导致阿尔茨海默病认知能力下降的确切机制尚不清楚。在这里，我们将淀粉样斑块相关的轴突球体确定为神经网络功能障碍的主要贡献者。使用活体钙和电压成像，我们展示了阿尔茨海默氏病小鼠模型显示远程轴突连接严重中断。这种中断是由动作电位传导阻滞引起的，这是由于扩大的球体以尺寸依赖的方式充当电流吸收器。球状体生长与大内溶酶体囊泡的年龄依赖性积累有关，并与Pld3有机械联系——一种潜在的阿尔茨海默氏病相关风险基因¹，编码溶酶体蛋白^2,3高度富含轴突球体。Pld3的神经元过度表达导致内溶酶体囊泡积聚和球体增大，这加剧了轴突传导阻滞。相比之下，PLD3缺失减少了内溶酶体囊泡和球体的大小，从而改善了电传导和神经网络功能。因此，神经元内溶酶体生物发生的靶向调节可能会逆转阿尔茨海默病中轴突球体诱导的神经回路异常，而与淀粉样蛋白去除无关。