FAIM-L SPATIAL LOCALIZATION AND PRESENCE IN SYNAPSES, WHERE IT MODULATES THEIR STRUCTURE AND FUNCTION, IS ALTERED IN TAU PATHOLOGY: INSIGHTS INTO THERAPEUTIC POSSIBILITIES

FAIM-L, is a neuron-specific anti-apoptotic protein isoform that stabilizes XIAP, regulating caspase-3 apoptotic and non-apoptotic functions and contributing to neuronal survival and synaptic plasticity. FAIM-L levels are reduced in Alzheimer’s disease, and in animal models of tauopathy before synaptic protein loss, suggesting that it may contribute to disease progression. Due to the lack of antibodies specific for this isoform, its localization and subcellular distribution have not been fully characterized. Here, we aimed to define the spatial and subcellular distribution of FAIM-L, focusing on its role in synapses and their alteration in tauopathy. FAIM-L expression was mapped using BaseScope, while protein subcellular localization was assessed by synaptic fractionation in WT, FAIM-KO, and P301S (PS19) tauopathy mice. FAIM-L synaptic functional impact was evaluated by hippocampal AAV-mediated FAIM-L delivery. FAIM-L RNA was enriched in the hippocampus (CA3) and detected in both excitatory and inhibitory neurons, whereas the protein showed preferential postsynaptic localization. In the retina, FAIM-L RNA was enriched in photoreceptor inner segments, while the protein was also present in isolated outer segments. PS19 mice exhibited reduced synaptic FAIM-L protein, while FAIM-KO mice showed altered synaptic XIAP distribution. Functionally, AAV-FAIM-L restored total dendritic spine density in PS19 mice and increased mushroom spine formation in WT animals in a sex-dependent manner, while also enhancing presynaptic facilitation and increasing synaptic proteins in WT mice. Together, these findings establish FAIM-L as a neuron- and synapse-associated protein, and support its role in regulating synaptic protein organization, stability and function in physiologic and pathologic conditions.