The non-genomic vitamin D pathway links β-amyloid to autophagic apoptosis in Alzheimer’s disease

Abstract

Vitamin D is an important hormonal molecule, which exerts genomic and non-genomic actions in maintaining brain development and adult brain health. Many epidemiological studies have associated vitamin D deficiency with Alzheimer’s disease (AD). Nevertheless, the underlying signaling pathway through which this occurs remains to be characterized. We were intrigued to find that although vitamin D levels are significantly low in AD patients, their hippocampal vitamin D receptor (VDR) levels are inversely increased in the cytosol of the brain cells, and colocalized with Aβ42 plaques, gliosis and autophagosomes, suggesting that a non-genomic form of VDR is implicated in AD. Mechanistically, Aβ42 induces the conversion of nuclear heterodimer of VDR/RXR heterodimer into a cytoplasmic VDR/p53 heterodimer. The cytosolic VDR/p53 complex mediates the Aβ42–induced autophagic apoptosis. Reduction of p53 activity in AD mice reverses the VDR/RXR formation and rescues AD brain pathologies and cognitive impairment. In line with the impaired genomic VDR pathway, the transgenic AD mice fed a vitamin D sufficient diet exhibit lower plasma vitamin D levels since early disease phases, raising the possibility that vitamin D deficiency may actually be an early manifestation of AD. Despite the deficiency of vitamin D in AD mice, vitamin D supplementation not only has no benefit but lead to exacerbated Aβ42 depositions and cognitive impairment. Together, these data indicate that the impaired genomic vitamin D pathway links Aβ42 to induce autophagic apoptosis, and suggest that VDR/p53 pathway could be targeted for the treatment of AD.