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

Abstract

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.

Vitamin D Reduces GABA-Positive Astrocytes in the 5xFAD Mouse Model of Alzheimer’s Disease

“…Our previous study suggests that a vitamin D-deficient state showed more brain Aβ load, caused by increasing Aβ production and decreasing Aβ degradation ( Supplementary Fig. 4 ) [ 8 ]. We also found increased Aβ plaques in the hippocampus of vitamin D-deficient 5XFAD mice.…”

“…The hippocampus has an important role in visuospatial memory [ 33 ], and aggravated Aβ pathology by vitamin D deficiency results in memory impairment in 5XFAD mice ( Supplementary Fig. 5 ) [ 8 ].…”

“…The experimental methodology used here has been described in detail in our earlier publication [ 8 ]. The 5XFAD mice were randomly assigned to six groups ( n = 6 per group): 1) Early-Control (Early-Con) group received a control diet (RodFeed, DBL, Eumseong, Korea) containing 60% carbohydrate, 20% protein, 4% fat, and 8 IU/kg vitamin D, in accordance with NIH-41 Open Formula.…”

Role of Vitamin D Deficiency in the Pathogenesis of Cardiovascular and Cerebrovascular Diseases

“…Additionally, the pathogenesis of AD itself also involves microvascular mechanisms; therefore, it is also considered a special form of VCI by many investigators [ 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 ]. In recent years, increasing evidence has been causally linked VDD to the genesis of VCI [ 166 , 167 ] and AD [ 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 ] in humans. Epidemiological studies suggest a more than doubled risk of mild cognitive impairment in older adults with VDD [ 178 , 179 , 180 , 181 , 182 ].…”

Reply to Pluta, R. Comment on “Minich et al. Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients 2022, 14, 3934”

“…Separate from the established and emerging research aiming to support the shared mechanisms of vitamin D and melatonin in brain- and neurological-related disorders, there is some indication that vitamin D may play a role in amyloid [ 30 , 31 , 32 , 33 , 34 ] and tau protein [ 35 , 36 , 37 ] metabolism, which are the distinct areas that Dr. Pluta showed particular interest in, and concern about, regarding our provocative statement of query as to whether melatonin is the “next vitamin D”.…”