Pld3-flox Mouse

Pld3, also known as HU-K4, encodes a lysosomal protein. It belongs to the phosphodiesterase family and is involved in synthesizing S,S-BMP, a key lysosomal phospholipid for lipid degradation, especially of gangliosides [3,5]. It may also be related to insulin-mediated phosphorylation of the AKT pathway [4].

In Alzheimer's disease (AD) research, neuronal overexpression of Pld3 led to endolysosomal vesicle accumulation and axonal spheroid enlargement, causing action-potential conduction blockades and neural network dysfunction. Conversely, Pld3 deletion reduced endolysosomal vesicle and spheroid size, improving electrical conduction and neural network function. These findings suggest that Pld3 could be a potential target for reversing axonal spheroid-induced neural circuit abnormalities in AD independent of amyloid removal [1]. Additionally, rare coding variants in Pld3 increase the risk for late-onset AD, and its level is downregulated in AD brains, negatively correlated with amyloid precursor protein (APP) and amyloid-β (Aβ) levels, hinting at its involvement in AD pathogenesis through APP processing [2].

In conclusion, Pld3 is crucial for lysosomal lipid degradation. Its study using gene knockout models has revealed its significant role in Alzheimer's disease, providing potential therapeutic targets for this neurodegenerative disorder. These models have been instrumental in understanding how Pld3 affects neural network function in the context of AD.