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

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 Alzheimers 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 A{beta}42 plaques, gliosis and autophagosomes, suggesting that a non-genomic form of VDR is implicated in AD. Mechanistically, A{beta}42 induces the conversion of nuclear heterodimer of VDR/RXR heterodimer into a cytoplasmic VDR/p53 heterodimer. The cytosolic VDR/p53 complex mediates the A{beta}42-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 A{beta}42 depositions and cognitive impairment. Together, these data indicate that the impaired genomic vitamin D pathway links A{beta}42 to induce autophagic apoptosis, and suggest that VDR/p53 pathway could be targeted for the treatment of AD. Significance StatementVitamin D exerts a genomic action for neuroprotection through VDR/RXR transcriptional complex. Thus, insufficient vitamin D has been linked to AD, but the signaling pathway involved remains unclear. Surprisingly, we find that the genomic action of VDR/RXR to be compromised and converted into a non-genomic VDR/p53 complex in promoting AD neurodegeneration. The cytosolic VDR/p53 complex contribute to autophagy-induced neuronal apoptosis. The VDR/RXR pathway can be a new therapeutic target for AD because targeting VDR/p53 ameliorates AD. Importantly, we provide evidence that vitamin D deficiency might be an early AD manifestation, and vitamin D supplementation exacerbates AD. This work uncovers a non-genomic VDR action in promoting AD and suggests a potential aggravating effect of vitamin D supplementation on AD.