TITLE: “Multi-tissue single-cell level understanding of Alzheimer’s disease points to the therapeutic potential of nutritional and metabolic modulation.”
ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by extracellular amyloid plaque deposition and intracellular neurofibrillary tangles. The direct cause of abnormal protein accumulation and aggregation is largely unknown, and no treatments exist to effectively delay or prevent development of AD. AD onset and progression is affected by many genetic and environmental factors, and exploration of significant risk factors for AD may help elucidate its complexity. AD is often comorbid with metabolic syndrome, which includes hypertension, elevated blood glucose and triglycerides, and abdominal obesity. We investigate the potential connection between AD and metabolic syndrome by testing the effect of high fructose consumption, omega-3 fatty acid docosahexaenoic acid (DHA), and nicotinamide riboside (NR) on hippocampal and hypothalamic single cell transcriptomes of the 5XFAD mouse model of amyloid accumulation. We report that metabolically challenging 5XFAD mice with fructose promotes expression of certain proinflammatory genes that may further exacerbate neuronal loss. Supplementation of 5XFAD with DHA and NR was shown to downregulate microglial activation genes, but DHA and NR on 5XFAD with fructose background also enhanced specific aspects of microglial function while downregulating fructose-induced exacerbation of proinflammatory genes, which may indicate mechanisms to counteract further worsening of AD by fructose. Overlaying differentially expressed genes (DEGs) onto a microglial gene regulatory network showed fructose, DHA, and NR target shared and specific aspects of the disease subnetwork. We also observed that fructose led to a depletion of an intermediate activated microglial state which was enhanced by DHA and NR. Transcriptomic signatures derived from this study showed high enrichment of GWAS signals including cell-type specific nutrition DEGs, regulatory network modules, and microglia trajectory associated genes. Our study has demonstrated that metabolic modulation impacts AD transcriptomic signatures and has significant implications for the treatment of AD with DHA and NR or modulators that enhance associated mechanisms.
