Chronic vitamin D3 supplementation alleviates cognition impairment via inhibition of oxidative stress regulated by PI3K/AKT/Nrf2 in APP/PS1 transgenic mice

• Vitamin D 3 ameliorate cognitive deficits and AD-related pathology of APP/PS1 transgenic mice. • Vitamin D 3 can activate the PI3K/AKT/Nrf2 pathway and facilitate nuclear translocation of Nrf2. • The activation of the PI3K/AKT/Nrf2 pathway is beneficial for alleviating oxidative stress. Oxidative stress plays essential role in the pathogenesis of Alzheimer's disease, and vitamin D 3 (VD 3 ) is a nutrient with neuroprotective and antioxidant activities. The present study aimed to confirm the neuroprotective effect and the ameliorative effect of cortical oxidative stress of VD 3 in APP/PS1 transgenic mice. APP/PS1 mice were treated with VD 3 for 20 weeks. After treatment, Morris Water Maze test was used to evaluate cognitive level. Western blotting was used to determine APP, p-tau, tau and PI3K/AKT/Nrf2 pathway-related protein expression levels. Immunohistochemical staining was performed to determine the levels of β amyloid peptide (Aβ) deposition. Enzyme linked immunosorbent assay was used to determine the 25(OH)D 3 levels and oxidative stress status. Our results showed that treatment with VD 3 ameliorated behavioral deficits of APP/PS1 mice. In addition, the administration of VD 3 significantly increased the cortical 25(OH)D 3 levels, while reducing the levels of cortical Aβ deposition and decreasing the expression levels of cortical APP, tau and p-tau in APP/PS1 mice. Moreover, VD 3 protected the cortex against oxidative stress by enhancing the levels of superoxide dismutase, glutathione and total antioxidant capacity, and downregulating the malondialdehyde levels. Furthermore, VD 3 clearly activated the PI3K/AKT/Nrf2 pathway, thereby elevating the expression levels of HO1 and NQO1. We concluded that VD 3 improved cognitive function and cortical Alzheimer-like pathology of APP/PS1 mice, which may be related to the inhibition of oxidative stress via activation the PI3K/AKT/Nrf2 pathway.