Single cell RNA sequencing of hippocampus and hypothalamus in AD mice with fructose-induced MetS and DHA and NR supplementation

Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder with hallmarks of beta-amyloid (Aβ) plaques and neurofibrillary tangles. In light of the suboptimal benefit of Aβ clearing drugs to patients, the association between metabolic disorders and AD provides an alternative angle to understand the role of metabolic dysfunction in AD pathogenesis and the potential of modulating metabolism for improved therapeutic development. We investigated the effects of metabolic and nutritional modulators, namely, high fructose consumption as a potential risk, and docosahexaenoic acid (DHA) and nicotinamide riboside (NR) as potentially beneficial, on cell type specific transcriptomic responses in the hippocampus and hypothalamus of an AD mouse model. Fructose-induced metabolic syndrome increased expression of complement component 3 in ependymal cells and inflammatory genes in microglia, which were normalized by DHA and NR. NR and DHA led to reversals of Aβ signatures across cell types and targeted different aspects of microglial reactivity between AD and metabolically challenged AD. Our study supports the impact of metabolic regulation on neuroinflammation and provides molecular support for utilizing metabolic modulators for AD intervention.