Regulation of lipid dysmetabolism and neuroinflammation linked with Alzheimer's disease through modulation of Dgat2

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by Amyloid-β (Aβ) plaque accumulation, cognitive decline, lipid dysregulation, and neuroinflammation. While mutations in the Amyloid Precursor Protein (APP) and Aβ42 accumulation contribute to AD, the mechanisms linking Aβ to lipid metabolism and neuroinflammation remain unclear. Using Drosophila models, we show that App ^NLG and Aβ42 expression causes locomotor deficits, disrupted sleep, memory impairments, lipid accumulation, synaptic loss, and neuroinflammation. Similar lipid and inflammatory changes are observed in the App ^NLG-F knock-in mouse model, reinforcing their role in AD pathogenesis. We identify diacylglycerol O-acyltransferase 2 (Dgat2), a key lipid metabolism enzyme, as a modulator of AD phenotypes. In Drosophila and mouse AD models, Dgat2 levels and its transcription factors are altered. Dgat2 knockdown in Drosophila reduced lipid accumulation, restored synaptic integrity, improved locomotor and cognitive function, and mitigated neuroinflammation. Additionally, Dgat2 modulation improved sleep and circadian rhythms. In App ^NLG-F mice, Dgat2 inhibition decreased neuroinflammation and reduced AD risk gene expression. These findings highlight the intricate link between amyloid pathology, lipid dysregulation, and neuroinflammation, suggesting that targeting Dgat2 may offer a novel therapeutic approach for AD. Conserved lipid homeostasis mechanisms across species provide valuable translational insights.