Neuroprotective Effect of 1α,25-Dihydroxyvitamin D3 Against Cognitive Impairment in <scp>d</scp>-Galactose-Induced Aging Mice

Aging and age-related cognitive impairment have emerged as a growing global public health concern, yet there are no effective preventive strategies. Excessive oxidative stress and neuroinflammation have been proven to contribute to cognitive decline. Vitamin D maintains the redox balance and exerts immunomodulatory effects, but the specific role of vitamin D in aging and age-related cognitive impairment remains elusive. This study explored the neuroprotective effects and the potential molecular mechanisms of 1α,25-dihydroxyvitamin D3 in the aging model. An aging model was established by the treatment of d-galactose for 14 weeks in male KM mice. 0.1, 0.5, or 1 μg/kg 1α,25-dihydroxyvitamin D3 were used in the intervention group for 8 weeks. Cognitive performance was evaluated using the Morris water maze test, and the levels of oxidative stress and neuroinflammation in the hippocampus were further analyzed. d-galactose induced memory impairment, whereas 1α,25-dihydroxyvitamin D3 intervention prevented cognitive decline, accompanied by a reduction in neuronal apoptosis, an enhancement of synaptic plasticity, and a decrease in Aβ deposition. Meanwhile, 1α,25-dihydroxyvitamin D3 dramatically attenuated oxidative stress, mitigated microglial cell activation, and ameliorated neuroinflammation by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (AREs) axis and inhibiting the NF-κB signaling pathway. This study provides evidence that 1α,25-dihydroxyvitamin D3 might be a promising nutritional strategy for preventing cognitive decline in aging, thereby facilitating the clinical application and expanding the insight of vitamin D.