How an altered PLD3-linked lysosomal catabolism impacts brain circuitry and Alzheimer’s pathology

Phospholipase D3 (PLD3) is a lysosomal exonuclease that targets mitochondrial DNA for degradation. Its late onset Alzheimer’s disease (LOAD)-linked loss-of-function causes an autophagic/lysosomal catabolic bottleneck (Van Acker, Nat. Comm., 2023). Whereas our unpublished spatial transcriptomics reveals a specific PLD3 expression in the hypothalamus and hippocampus, PLD3 is known to be respectively down- and upregulated in neurons and activated microglia of AD brains. Hence, in this project, I will unravel the cell-type specific molecular mechanisms linking PLD3’s lysosomal function to neuronal connectivity and synaptic transmission, and how this may connect to microglia activation. Using our new PLD3xAPP knock-in mouse and human iPSC models, I will exploit our strengths in advanced microscopy, xenotransplantation and subcellular spatial transcriptomics. I will map the spatial crosstalk between a derailed lysosomal nucleotide catabolism and AD pathology in both neurons and microglia. Interestingly, with both an impaired endolysosomal homeostasis and circadian disruption to occur early in the course of the disease, I hypothesize that the project's results will link a number of the disparate or seemingly unconnected brain regions and cells/cell functions.