Journal Article

Non‐genomic rewiring of vitamin D receptor to p53 as a key to Alzheimer's disease

Huang, Che‐Ching, Lai, Rai‐Hua, Hsu, Yueh‐Ying, Shie, Feng‐Shiun, Juang, Jyh‐Lyh, Chen, Mei‐Hsin

2021

Overview

Observational epidemiological studies have associated vitamin D deficiency with Alzheimer's disease (AD). However, whether vitamin D deficiency would result in some impacts on the vitamin D binding receptor (VDR) remains to be characterized in AD. Vitamin D helps maintain adult brain health genomically through binding with and activating a VDR/retinoid X receptor (RXR) transcriptional complex. Thus, we investigated the role of VDR in AD using postmortem human brains, APP/PS1 mice, and cell cultures. Intriguingly, although vitamin D was decreased in AD patients and mice, hippocampal VDR levels were inversely increased. The abnormally increased levels of VDR were found to be colocalized with Aβ plaques, gliosis and autophagosomes, implicating a non‐genomic activation of VDR in AD pathogenesis. Mechanistic investigation revealed that Aβ upregulated VDR without its canonical ligand vitamin D and switched its heterodimer binding‐partner from RXR to p53. The VDR/p53 complex localized mostly in the cytosol, increased neuronal autophagy and apoptosis. Chemically inhibiting p53 switched VDR back to RXR, reversing amyloidosis and cognitive impairment in AD mice. These results suggest a non‐genomic rewiring of VDR to p53 is key for the progression of AD, and thus VDR/p53 pathway might be targeted to treat people with AD. In Alzheimer’s brain, Aβ induces a non‐genomic action of vitamin D receptor (VDR) via switching VDR heterodimer partner from retinoid X receptor (RXR) to p53, in impairing autophagosome processing. Pharmacological inhibition of p53 switches VDR back to interaction with RXR and diminishes Aβ plaque load and cognitive deficits.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Alzheimer Disease - genetics / Alzheimer Disease - physiopathology / Alzheimer's disease / Amyloidosis / Animals / Apoptosis / Autophagy / Autophagy - genetics / Cognitive ability / Cytosol / Epidemiology / Genomics / Gliosis / Hippocampus / Humans / Mice / Neurodegenerative diseases / non‐genomic vitamin D receptor / Original Paper / Original Papers / p53 / p53 Protein / Phagocytosis / Phagosomes / Presenilin 1 / Retinoid X receptors / Senile plaques / Transcription / Tumor Suppressor Protein p53 - metabolism / Vitamin D / Vitamin D - metabolism / Vitamin D Deficiency - complications / Vitamin D receptors / Vitamin deficiency