Abstract
Alzheimers disease (AD) is a progressive neurodegenerative disorder marked by amyloid-beta; (ab-42) plaque accumulation, cognitive decline, lipid dysregulation, and neuroinflammation. While mutations in the Amyloid Precursor Protein (APP) and Ab-42 accumulation contribute to AD, the mechanisms linking Ab-42; to lipid metabolism and neuroinflammation remain unclear. Using Drosophila models, we show that AppNLG and Ab-42 expression causes locomotor deficits, disrupted sleep, memory impairments, lipid accumulation, synaptic loss, and neuroinflammation. Similar lipid and inflammatory changes are observed in the AppNLG-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 AppNLG-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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
We have updated several figure panels for clarity and with updated statistics. We have also significantly reduced the manuscript length to provide a more concise and clear message.
