PLD3 affects axonal spheroids and network defects in Alzheimer's disease.

ABSTRACT: 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 i

SUBMITTER: Yuan P 

PROVIDER: S-EPMC9729106 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature