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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\u00a0mice, 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 A\u03b2 plaques, gliosis and autophagosomes, implicating a non\u2010genomic activation of VDR in AD pathogenesis. Mechanistic investigation revealed that A\u03b2 upregulated VDR without its canonical ligand vitamin D and switched its heterodimer binding\u2010partner from RXR to p53. The VDR\/p53 complex localized mostly in the cytosol, increased neuronal autophagy and apoptosis. Chemically inhibiting p53\u00a0switched VDR back to RXR, reversing amyloidosis and cognitive impairment in AD mice. These results suggest a non\u2010genomic 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.<\/jats:p>","DOI":"10.1111\/acel.13509","type":"journal-article","created":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T07:42:27Z","timestamp":1635838947000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Non\u2010genomic rewiring of vitamin D receptor to p53 as a key to Alzheimer's disease"],"prefix":"10.1111","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5608-6921","authenticated-orcid":false,"given":"Rai\u2010Hua","family":"Lai","sequence":"first","affiliation":[{"name":"Institute of Molecular and Genomic Medicine National Health Research Institutes  Zhunan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueh\u2010Ying","family":"Hsu","sequence":"additional","affiliation":[{"name":"Institute of 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