Alzheimer's disease associated Presenilin 2 N141I mutation impairs neuronal lipid homeostasis and mitochondrial dynamics through selective downregulation of the Golgi exchange factor Gbf1

Presenilin 2 (PS2) mutations cause familial Alzheimer's disease, yet their effects beyond amyloid processing remain poorly understood. Here, we investigated how PS2 deletion and the N141I mutation affect neuronal lipid homeostasis and mitochondrial dynamics using PS2-deficient and PS2-mutant (N141I) mouse primary neurons. Both PS2 deletion and N141I mutation reduced neuronal lipid content; however, exogenous lipid supplementation rescued the deficit only in N141I-expressing neurons, indicating a partial loss-of-function. Furthermore, N141I neurons displayed reduced OPA1, a mitochondrial fusion regulator, which was restored by lipid supplementation. RNA-sequencing identified Gbf1, a Golgi-specific guanine nucleotide exchange factor, as selectively downregulated in N141I but not knockout tissue, which was confirmed at protein level in mouse brain and primary neurons. These results reveal a PS2-Gbf1-mitochondria axis disrupted specifically by the N141I mutation, suggesting an amyloid-independent pathway contributing to neurodegeneration and identifying potential therapeutic targets for familial Alzheimer's disease.