Neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD) pose a major global challenge, with few effective therapies available. The genetic PLCG2-P522R variant exerts protection against AD and FTD and is associated with increased longevity. PLCG2 encodes PLC?2, a microglial signaling enzyme now linked also to neuronal and metabolic functions, positioning its activation as a promising therapeutic strategy. However, mechanisms underlying PLC?2-P522R-mediated protection remain unclear. The DEFEND project addresses this through integrated approaches by examining (1) immunometabolic resilience in Trem2-deficient mice under dietary stress; (2) genetic risk interactions using iPSC-derived microglia-neuron models; (3) variant effects on imaging, biomarker, and health data in Finnish biobank cohorts. These studies will define PLC?2-driven pathways enhancing resilience against neurodegeneration.

2026

2030