Impact of Vitamin D on Amyloid Precursor Protein Processing and Amyloid-β Peptide Degradation in Alzheimer's Disease

Abstract

Ninety percent of the elderly population has a vitamin D hypovitaminosis, and several lines of evidence suggest that there might be a potential causal link between Alzheimer's disease (AD) and a non-sufficient supply with vitamin D. However, the mechanisms linking AD to vitamin D have not been completely understood. The aim of our study is to elucidate the impact of 25(OH) vitamin D₃ on amyloid precursor protein processing in mice and N2A cells utilizing very moderate and physiological vitamin D hypovitaminosis in the range of 20-30% compared to wild-type mice. We found that already under such mild conditions, amyloid-β peptide (Aβ) is significantly increased, which is caused by an increased β-secretase activity and BACE1 protein level. Additionally, neprilysin (NEP) expression is downregulated resulting in a decreased NEP activity further enhancing the effect of decreased vitamin D on the Aβ level. In line with the in vivo findings, corresponding effects were found with N2A cells supplemented with 25(OH) vitamin D₃. Our results further strengthen the link between AD and vitamin D₃ and suggest that supplementation of vitamin D₃ might have a beneficial effect in AD prevention.

The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease

“…Rodents fed with vitamin D 3 -enriched diets show a significant reduction of brain Aβ burden along with improved cognitive performances [76,77,78]. Inversely, we and others observed an increase of the Aβ40 and Aβ42 content in the brain tissue of vitamin D-deficient animals [78,79]. This is in line with the observation that vitamin D deficiency strengthens the spatial learning deficits of rats after intracerebroventricular Aβ42-injection.…”

Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact

“…Therefore, in line with Buell and Dawson-Hughes [169], calcium concentrations are not likely to vary in the different haplotypes, indicating a protective effect on the brain, beyond the calcium homeostasis. Thus, in the Alzheimer disease culture models, VDH stimulates the amyloid plaques [170,171], supporting the phagocytosis induced by macrophages of a soluble amyloid beta protein [171,172], and reduces the inflammation response induced by amyloid deposition [21]. Lipopolysaccharide-induced levels of mRNA encoding for macrophage colony stimulating factors and tumor necrosis factors in cultured astrocytes are partially reduced after vitamin D treatment [21].…”

“…Moreover, as previously described, vitamin D regulates the expression of 74 genes and 36 proteins, connected with the correct development of the cytoskeleton and exerting a regulation on post-transcriptional controls for L-type voltage-sensitive calcium channels [196,197]. All of the effects of vitamin D on the vascular system link it to vascular dementia in many different ways, such as: epidemiological [198], based on vascular pressure control [191], based on biological properties of vitamin D, above described [199], or simply considering vitamin D deficiency as a risk-modifiable factor [170,200,201]. It seems quite interesting that the three works that link the vitamin D defect to small vessel disease-related dementia [188,189] stand on two axiomatic biological properties, the anti-oxidative capacity of vitamin D (therefore a loss of protection against Reactive Oxygene Species (ROS), whenever it lacks), and the control of the smooth vessel, which is fundamental for auto-regulation in brain circulation.…”

Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact

“…Thus, in Alzheimer disease culture models, VDH stimulates amyloid plaques [202], supporting the phagocitosis induced by macrophages of soluble amyloid beta protein [203] and reduces the inflammation response, induced by amyloid deposition [16].…”