GALECTIN-3 DEFICIENCY ATTENUATES DISEASE PROGRESSION IN PGRN-DEPENDENT FTD MICE

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders characterized by progressive frontal and temporal lobe atrophy, abnormal protein aggregation, and chronic neuroinflammation. It is the second most common cause of early-onset dementia after Alzheimer’s disease and presents with prominent behavioral, language, and executive impairments. FTD occurs sporadically or through inherited mutations, most frequently in C9orf72, GRN, or MAPT, and is pathologically classified by Tau, TDP-43, or FET protein inclusions. Beyond neuronal loss, FTD is associated with lipofuscin accumulation, white matter degeneration, gliosis, and marked microglial activation. PET imaging and postmortem studies reveal increased microglial activity, particularly in white matter tracts, highlighting a potential role in disease progression. Galectin-3 (Gal-3) is a regulator of microglial activation and has emerged as a key mediator of neuroinflammation in FTD. Gal-3 is significantly upregulated in cortical tissue from MAPT and GRN mutation carriers, but not in C9orf72 cases, and cerebrospinal fluid Gal-3 levels are elevated in sporadic FTD, especially in the behavioral variant. Mouse models further demonstrate Gal-3 positive microglial activation in white matter regions and an association with lipofuscin accumulation, linking Gal-3 to microglial dysfunction and white matter pathology. We hypothesize that sustained Gal-3 dependent proinflammatory microglial activation is a critical early event that disrupts myelin integrity, impairs neuronal function, and accelerates pathological progression in FTD. This project aims to define the mechanistic role of Gal-3 in microglial dysfunction and evaluate its potential as a biomarker and therapeutic target.