Hippocampal and hypothalamic cell-type specific mechanisms underlying nutritional and metabolic modulation of Alzheimer’s disease

To understand the potential of modulating metabolism for therapeutic development for Alzheimer's disease (AD), we investigated the effects of 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 the 5xFAD mouse model. Fructose increased the expression of C3 , encoding complement component 3, in ependymal cells and inflammatory genes in microglia, which were normalized by DHA and NR. NR and DHA reversed Aβ-associated transcriptional signatures across cell types, but the effects were modified by fructose. DHA and NR treatments reversed the AD-associated decrease in hippocampal oligodendrocytes, with DHA further reducing hippocampal microglia and increasing hypothalamic astrocytes, and NR further increasing hippocampal neuronal proportions. Our study supports the impact of metabolic regulation of AD-associated cell types and pathways and provides molecular support for utilizing nutritional modulators for AD intervention.