CD300F IN ALZHEIMER’S DISEASE: FUNCTIONAL IMPACT OF RECEPTOR DEFICIENCY IN MICE AND PATHWAY ASSOCIATIONS IN HUMAN BRAIN SAMPLES

Microglia are key players in neuroinflammation and amyloid-β (Aβ) handling in Alzheimer’s disease (AD), while peripheral myeloid cells can also influence disease progression. CD300f is a lipid-binding myeloid immune receptor with inhibitory and activating signalling roles, involved in DAMP sensing, phagocytosis, lipid metabolism and inflammatory regulation. However, its contribution to AD pathology remains poorly understood. Here, we investigated the impact of CD300f deficiency on AD pathology using the 5xFAD mouse model and complementary in vitro approaches. Cognitive performance was assessed using a behavioural test battery, and β-myeloid pathology was analysed by immunofluorescence. In parallel, the phagocytic capacity of WT and CD300f-/- macrophages exposed to Aβ and myelin was evaluated. Possible interactions between human CD300f and Aβ were examined using immunoassays. Potential convergence between CD300f and TREM2 pathways was explored in human AD brain samples by proteomic analyses. CD300f-deficient 5xFAD mice exhibited exacerbated functional decline compared to control mice, suggesting a protective role for CD300f. In vitro, macrophages lacking CD300f showed reduced intracellular Aβ after prolonged exposure. However, sandwich ELISA assays did not support a direct interaction between CD300f and Aβ, in contrast to the established Aβ-binding receptor TREM2. Proteomic analyses of CD300f immunoprecipitated from human AD samples revealed associations with proteins involved in metabolic regulation, immune signalling, mitochondrial pathways and neuron–glia crosstalk, many overlapping with the reported TREM2 interactome. Overall, these findings indicate that CD300f modulates myeloid cell responses relevant to AD progression, potentially through pathways converging with TREM2 rather than direct Aβ binding.