INTRODUCTION: Ceramides are lipids that serve as key structural components of cell membranes and regulate cell proliferation, differentiation, and apoptosis. Ceramide transfer proteins (CERTs) transport ceramide from the endoplasmic reticulum (ER) to the Golgi apparatus for sphingomyelin synthesis and signalling molecule production. CERTs are crucial for embryogenesis, brain development, and immunoglobulin-independent complement pathway activation. Recent studies show ceramides stabilize β- and γ-secretases, enzymes that cleave amyloid precursor protein (APP) to generate toxic amyloid-β (Aβ). Post-mortem Alzheimer’s disease brains exhibit increased ceramide and related enzymes, with decreased sphingomyelins in membrane lipid rafts. In vitro, CERT binds APP and modulates Aβ aggregation, while CERT-overexpressing mouse models show reduced Aβ formation and attenuated microglial proinflammatory responses.

AIM(S): To investigate CERT’s cell-autonomous functions in microglia, given their role in Alzheimer’s disease and lipid dysregulation.

METHOD(S): We generated mice with floxed CERT1 alleles and excised CERT1 in microglia using Cx3cr1-Cre. Memory performance, microglial morphology (high-resolution microscopy), and inflammatory markers were assessed.

RESULTS: Microglia lacking CERT1 adopted an inflammatory morphology with elevated iNOS and CD68 expression, correlating with cognitive deficits in declarative memory tasks.

CONCLUSIONS: RNAseq analysis of purified microglia will elucidate molecular mechanisms underlying this phenotype.