Alzheimer's disease (AD), the most common neurodegenerative dementia, involves Presenilins (PS) 1 and 2, which are pivotal in amyloid-β (Aβ) production and amyloid pathology. PS functions, associated with inherited AD (FAD), extend beyond Aβ production. PS2 in particular is critical in mitochondrial function and cell bioenergetics. Here, we aim to explore Presenilins' role in cellular lipid metabolism.Brain samples were collected from WT, PS2 +/-, PS2 -/- and PS2N141I mice, carrying the FAD N141I mutation. We evaluated LPL and nSMase 2 levels based on preliminary data indicating their upregulation in PS2 -/- MEFs. We then assessed the lipid profile in WT, PS1- and PS2-deficient SH-SY5Y cells using PhenoVue Nile Red lipid stain. The same staining was performed on coronal brain sections.No differences in LPL and nSMase2 levels were found between groups, suggesting limitations in extrapolating results from cell lines to mouse samples. Lipidic cytoplasmic inclusions were detected in SH-SY5Y cells, with significantly higher fluorescence intensity in PS2KD compared to WT (p < 0.005) and PS1KD (p < 0.05). In mouse samples, extracellular lipidic aggregates were observed in subregions of the hippocampal formation: the stratum-lacunosum moleculare (SLM) and the molecular layer of the subiculum (SubM). While no differences in fluorescence intensity were noted in the SLM among groups, a significant increase was observed in the SubM of PS2 -/- compared to WT (p < 0.05).Altogether, data suggest a potential effect of PS2 deletion on the lipid profile. PS2 mutation might have more nuanced influences, currently investigated in lipidomic analyses.