The Role of Vitamin D in Alzheimer’s Disease: A Transcriptional Regulator of Amyloidopathy and Gliopathy

Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) accumulation and cognitive mental decline. Epidemiological studies have suggested an association between low serum vitamin D levels and an increased risk of AD. Vitamin D regulates gene expression via the vitamin D receptor, a nuclear ligand-dependent transcription factor. However, the molecular mechanism underlying the pathogenic and therapeutic effects of vitamin D on AD is not fully understood yet. To better understand how vitamin D regulates the expression of genes related to AD pathology, first, we induced vitamin D deficiency in 5xFAD mice by providing a vitamin-D-deficient diet and observed the changes in the mRNA level of genes related to Aβ processing, which resulted in an increase in the Aβ load in the brain. The vitamin D-deficient diet also suppressed the expression of genes for microglial Aβ phagocytosis. Interestingly, vitamin D deficiency in the early stage of AD resulted in earlier memory impairment. In addition, we administered vitamin D intraperitoneally to 5xFAD mice with a normal diet and found lower Aβ levels with the suppressed expression of genes for Aβ generation and observed improved memory function, which may be potentially associated with reduced MAO-B expression. These findings strongly suggest the role of vitamin D as a crucial disease-modifying factor that may modulate the amyloid pathology with regard to reducing AD symptoms.