PLCG2 Variants and Their Implications in Alzheimer's Disease

To identify the roles that two PLCG2 variants play in the development and progression of microtubule-associated protein tau aggregates, cell death, and memory loss in Alzheimer’s disease.

PLCG2, an enzyme that is important in cell-to-cell communication, also plays a role in the risk of developing late-onset Alzheimer’s disease (AD). The gene that encodes for this enzyme has AD-associated variants: one of which protects against AD, and one of which promotes AD. We aim to identify the role that these two AD-associated PLCG2 variants play in the development and progression of microtubule-associated protein tau aggregates, cell death, and memory loss.

First, this will be the first study to investigate the potential mechanisms underlying the role of PLCG2 AD variants in tau processing and neuronal death, beyond their established role in microglia. Second, we will use humanized AD-like mice, autophagy reporter mice, and Visium HD spatial transcriptomics at the single-cell level to study the role of PLCG2 AD variants in vivo. Finally, we will use the human neural organoid model to validate the role of PLCG2 AD variants in human tau processing and neuronal functions.

This research will advance our understanding of the precise role that PLCG2 variants play in Alzheimer’s disease, which may guide the development of therapeutics that target PLCG2 and the related autophagy-lysosome pathway to prevent, treat, and/or delay this devastating disease.