Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity

Free Radic Biol Med. 2020 Dec;161:139-149. doi: 10.1016/j.freeradbiomed.2020.10.007. Epub 2020 Oct 14.

Abstract

Vitamin D (VD) deficiency is prevalent among aging people and Alzheimer's disease (AD) patients. However, the roles of VD deficiency in the pathology of AD remain largely unexplored. In this study, APP/PS1 mice were fed a VD-deficient diet for 13 weeks to evaluate the effects of VD deficiency on the learning and memory functions and the neuropathological characteristics of the mice. Our study revealed that VD deficiency accelerated cognitive impairment in the APP/PS1 mice. Mechanistic studies revealed that VD deficiency promoted glial activation and increased inflammatory factor secretion. Furthermore, VD deficiency increased the production and deposition of Aβ by elevating the expression levels of amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1). In addition, VD deficiency increased the phosphorylation of Tau at Thr181, Thr205 and Ser396 by increasing the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3α/β (GSK3α/β) and promoted synaptic dystrophy and neuronal loss. All these effects of VD deficiency may be ascribed to enhanced oxidative stress via the downregulation of superoxide dismutase 1 (SOD1), glutathione peroxidase 4 (GPx4) and cystine/glutamate exchanger (xCT). Taken together, our data suggest that VD deficiency exacerbates Alzheimer-like pathologies via promoting inflammatory stress, increasing Aβ production and elevating Tau phosphorylation by decreasing antioxidant capacity in the brains of APP/PS1 mice. Hence, rescuing the VD status of AD patients should be taken into consideration during the treatment of AD.

Keywords: Alzheimer's disease; Oxidative stress; Tau; Vitamin D deficiency; β-amyloid protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / genetics
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Antioxidants
  • Aspartic Acid Endopeptidases
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Presenilin-1
  • Vitamin D Deficiency*
  • tau Proteins / genetics

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Antioxidants
  • Presenilin-1
  • tau Proteins
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases