SEX-SPECIFIC BENEFICIAL EFFECTS OF FAIM-L ON BEHAVIORAL DEFICITS IN A TAUOPATHY MOUSE MODEL

Alzheimer’s disease (AD) is a common neurodegenerative disease with significant sex difference in incidence. One of its core pathologies is the hyperphosphorylation and aggregation of Tau protein, which is closely associated with neuronal death and cognitive impairment. FAIM-L is a neuron-specific endogenous antiapoptotic protein whose levels are reduced in the hippocampus of AD patients and in mouse models with tau pathology, but not in those with b-amyloid pathology. These observations, combined with the crucial role of FAIM-L in neuronal survival, synaptic plasticity and proteostasis, suggest that its downregulation may promote AD progression so it might be used as therapeutic target.
In this study, we characterized FAIM-L levels and other neurodegeneration-related molecules in the P301S (PS19) mouse model across ages and sex. We further restored FAIM-L expression via hippocampal injection of AAVs-FAIM-L to assess its therapeutic role. FAIM-L levels in the hippocampus started a progressive decline from in 6 months, whereas other neurodegenerative traits such as synaptic proteins loss or neuroinflammation were detected from 9 months, and more pronounced in males. FAIM-L ameliorated habituation deficits in both sexes, while preventing associative memory impairment only in females and improving discrimination capacity in males. Additionally, FAIM-L enhanced neuronal survival in the dentate gyrus of PS19 mice.
Overall, FAIM-L loss precedes Tau-related pathological changes, with more severe changes in male PS19 mice, while its restoration improves cognition in a sex-dependent manner. These findings highlight the importance of sex differences and FAIM-L as a potential therapeutic target in tauopathy.