Curcumin Mitigates the High-Fat High-Sugar Diet-Induced Impairment of Spatial Memory, Hepatic Metabolism, and the Alteration of the Gut Microbiome in Alzheimer's Disease-Induced (3xTg-AD) Mice

The escalating prevalence of metabolic diseases and an aging demographic has been correlated with a concerning rise in Alzheimer's disease (AD) incidence. This study aimed to access the protective effects of curcumin, a bioactive flavonoid from turmeric, on spatial memory, metabolic functions, and the regulation of the gut microbiome in AD-induced (3xTg-AD) mice fed with either a normal chow diet (NCD) or a high-fat high-sugar diet (HFHSD). Our findings revealed an augmented susceptibility of the HFHSD-fed 3xTg-AD mice for weight gain and memory impairment, while curcumin supplementation demonstrated a protective effect against these changes. This was evidenced by significantly reduced body weight gain and improved behavioral and cognitive function in the curcumin-treated group. These improvements were substantiated by diminished fatty acid synthesis, altered cholesterol metabolism, and suppressed adipogenesis-related pathways in the liver, along with modified synaptic plasticity-related pathways in the brain. Moreover, curcumin enriched beneficial gut microbiota, including Oscillospiraceae and Rikenellaceae at the family level, and Oscillibacter, Alistipes, Pseudoflavonifractor, Duncaniella, and Flintibacter at the genus level. The observed alteration in these gut microbiota profiles suggests a potential crosswalk in the liver and brain for regulating metabolic and cognitive functions, particularly in the context of obesity-associated cognitive disfunction, notably AD.