Abstract
Alzheimer's disease (AD), an age-associated neurodegenerative disorder, is characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation (including soluble oligomers and deposited aggregates), lipid dysregulation, and neuroinflammation. Although mutations in the amyloid precursor protein (APP) and accumulation of Aβ42 are established drivers of pathology, the mechanisms connecting oligomeric amyloid toxicity with lipid metabolism and inflammatory responses remain poorly understood. Here, we employed complementary Drosophila and mouse models to dissect these relationships. Panneuronal, glial or mushroom body specific expression of humanized App[NLG] and Aβ42 in Drosophila resulted in locomotor deficits, disrupted sleep-circadian rhythms, memory impairments, lipid accumulation, synaptic loss, and neuroinflammatory signatures. Comparable lipid accumulation, metabolic dysregulation and neuroinflammation were detected in the App[NLG-F] knock-in mouse model, underscoring their conserved relevance to AD pathogenesis. We further identified diacylglycerol O-acyltransferase 2 (Dgat2), a key enzyme catalyzing the final step of triglyceride synthesis, as a critical modulator of AD-related phenotypes. Dgat2 expression was altered in both animal models and human AD tissues. Notably, panneuronal knockdown of Dgat2 in Drosophila attenuated lipid accumulation, restored synaptic integrity, and ameliorated locomotor and cognitive deficits, while also reducing neuroinflammation. Additionally Dgat2 suppression improved sleep and circadian behavior, highlighting its pleiotropic protective effects. Together, these findings support a mechanistic link between amyloid pathology, lipid dysregulation, and neuroinflammatory processes. The conservation of lipid homeostasis mechanisms across species underscores the translational potential of this approach for delaying or mitigating AD progression. Moreover, targeting Dgat2 may therefore represent a novel therapeutic strategy to counteract AD-associated metabolic and neuronal dysfunction.
