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

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque accumulation, cognitive decline, lipid dysregulation, and neuroinflammation. Mutations in the Amyloid Precursor Protein (APP), and accumulation of A contribute to AD, however, underlying mechanisms linking beta amyloid to lipid metabolism and neuroinflammation remain unclear. Using models, we demonstrate that and lead to progressive locomotor impairments, disrupted sleep activity, memory deficits, lipid dysregulation, loss of synaptic integrity, and neuroinflammation. Lipid accumulation and neuroinflammation have also been observed in the knockin mouse model, supporting their involvement in AD pathogenesis. Furthermore, we demonstrate a role of Diacylglycerol O-acyltransferase 2 (Dgat2), a key enzyme in lipid regulation, in modulating AD phenotypes, as Dgat2 and the levels of its potential transcription factors were altered in AD Drosophila and mouse models. In and AD models, knockdown reduced lipid accumulation, restored synaptic integrity, improved locomotor and cognitive function, and attenuated neuroinflammation. Additionally, Dgat2 modulation improved sleep quality and circadian rhythms, further implicating lipid metabolism in AD progression. In mice, Dgat2 inhibition mitigated lipid dysmetabolism decreased neuroinflammatory responses, and reduced expression of AD risk genes. These findings underscore the intricate interplay between amyloid pathology, lipid dysregulation, and neuroinflammation, and suggest that targeting Dgat2 may provide a novel therapeutic strategy for mitigating AD-associated dysfunction. Understanding the conserved impact of lipid homeostasis across species offers valuable insights into potential translational interventions for AD.