Vitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation

Int J Mol Sci. 2017 Dec 19;18(12):2764. doi: 10.3390/ijms18122764.


Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aβ-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D₂ and D₃ analogues decreased Aβ-production and increased Aβ-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aβ-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased β-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.

Keywords: Aβ-degradation; amyloid precursor protein; amyloid-β; secretases; vitamin D; vitamin D analogues.

MeSH terms

  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Cell Line, Tumor
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Plaque, Amyloid / drug therapy*
  • Proteolysis*
  • Vitamin D / administration & dosage
  • Vitamin D / pharmacology
  • Vitamin D / therapeutic use*
  • Vitamins / administration & dosage
  • Vitamins / pharmacology
  • Vitamins / therapeutic use*


  • Amyloid beta-Peptides
  • Vitamins
  • Vitamin D
  • Amyloid Precursor Protein Secretases