Nicotinamide riboside alleviates sweeteners-induced brain and cognitive impairments in immature mice

The consumption of sweeteners is high around the world. Sweet beverages are one of the most important and popular sources of sweeteners. Previous studies have reported that excessive sweeteners might cause health hazards, including cognitive impairment. Nicotinamide riboside (NR), a precursor of NAD⁺, has been found to alleviate several cognitive impairments. However, the protective effects of NR against sweetener-induced cognitive impairment remain unclear. Hence, we evaluated the effects of sweeteners and NR (400 mg kg^-1 d^-1) on the brain and cognition of mice by simulating an extreme lifestyle of completely replacing water with sugar-sweetened beverage (simulated with 10% sucrose solution) or sugar-free sweet beverage (simulated with 0.05% aspartame solution) from weaning to adulthood. The results revealed that continuous exposure to sucrose or aspartame for eight weeks did not significantly cause differences in body weight but significantly induced cognitive impairments, including anxiety- and depressive-like behaviours, impairments in learning, memory and sociability. Moreover, sucrose or aspartame exposure induced neuronal injury, reduction of Nissl bodies, overactivation of the TLR4/NF-κB/NLRP3/ASC/Caspase-1 pathway and increased downstream inflammatory cytokines in mouse hippocampus, and also induced an imbalance of oxidative stress, apoptosis and autophagy, large consumptions of intracellular antioxidant factors, and overactivation of the PI3K/Akt/FOXO1 and PI3K/Akt/mTOR pathways in mouse brain. NR treatment increased NAD⁺ in the brain, and prevented and alleviated these impairments effectively. In summary, we found that NR supplementation protected against cognitive impairment caused by sucrose or aspartame in immature mice, which might be related to increased brain NAD⁺ level, relieved neuroinflammation and pyroptosis in the hippocampus, and maintained a balance of oxidative stress, apoptosis and autophagy in the brain.