Long-term oral administration of dietary carotenoids mixture alleviates cognitive impairment and AD neuropathology in APP/PS1 mice

Specific carotenoid (e.g., β-carotene, lutein, lycopene) has potential benefits for cognitive health demonstrated in both human and animal studies, yet higher dose of β-carotene supplementation exhibited detrimental health outcomes in large-scale intervention studies. To mimic the composition of carotenoids in the human diet and to avoid the overdose of any specific carotenoid, we developed a mixture of 6 carotenoids (7.5mg/kg/d, including 9.0% α-carotene, 35.8% β-carotene, 12.2% lutein, 1.6% zeaxanthin, 41.0% lycopene and 0.4% β-cryptoxanthin) and investigated its long-term neuroprotective effect and explored potential underlying mechanism in APP/PS1 mice, a well-established animal model for Alzheimer’s disease. Initiated at 3 months with a total of 4 months’ gavage intervention, the dietary carotenoids mixture was found to alleviate cognitive impairment and Aβ deposition in the brain (P < 0.05). Consistently, dietary carotenoids mixture restored Nissl bodies and the density of dendritic spines, and increased protein expression of Synapsin and PSD95 in the hippocampus and cortex of APP/PS1 mice (P < 0.05). In addition, carotenoids were also found to reduce oxidative stress and inflammation level and increase autophagy (P < 0.05). Importantly, carotenoids have been shown to up-regulate the expression of SIRT1 and BDNF in the brain (P < 0.05). Together, long-term intake of dietary carotenoids mixture could alleviate the cognitive deficit in APP/PS1 mice, wherein the SIRT1/BDNF pathway might play an essential role. Our findings could contribute to the development of effective dietary and nutritional intervention strategies for delaying neurodegeneration in the aging population.