Aging is associated with behavioral alterations, lysosomal dysfunction, region-specific inflammation, and glutamatergic synaptic impairments in a Grn knockout mouse model of frontotemporal dementia

Abstract Progranulin-related frontotemporal dementia ( GRN -FTD) is an inherited neurodegenerative disorder caused by progranulin (PGRN) deficiency. Although PGRN functions are well characterized and several therapeutic strategies aiming to restore its levels are currently under evaluation, the mechanisms linking PGRN loss to neurodegeneration remain unclear. Exploiting a Grn knockout mouse model, we first investigated the impact of PGRN deficiency on behaviour longitudinally (4, 6, 9, and 12 months), then, at 12 months of age, the final time point assessed, we examined glucocerebrosidase (GCase) activity and consequent glucosylsphingosine (GS) accumulation, neuroinflammation, and molecular/morphological alterations at glutamatergic synapses. Grn -mutant mice displayed genotype-specific, age-dependent impairments in pheromone perception, memory deficits, and increased aggression. Reduced GCase activity and GS accumulation confirmed lysosomal dysfunction, which was associated with brain-region-specific alterations in AMPA- and NMDA-type glutamate receptor levels and reduced dendritic spine density, the latter observed only in Grn +/− mice. These findings identify PGRN-related lysosomal dysfunction as a contributing factor to circuit disruption and behavioural deficits, highlighting the need for combinatorial therapeutic strategies going beyond PGRN replacement.