Ribosylation-Derived Advanced Glycation End Products Induce Tau Hyperphosphorylation Through Brain-Derived Neurotrophic Factor Reduction

J Alzheimers Dis. 2019;71(1):291-305. doi: 10.3233/JAD-190158.

Abstract

Advanced glycation end products (AGEs) have been implicated in the disease process of diabetes mellitus. They have also been found in senile plaques and neurofibrillary tangles in the brains of Alzheimer's disease patients. Furthermore, abnormally high levels of D-ribose and D-glucose were found in the urine of patients with type 2 diabetes mellitus, suggesting that diabetic patients suffer from dysmetabolism of not only D-glucose but also D-ribose. In the present study, intravenous tail injections of ribosylated rat serum albumin (RRSA) were found to impair memory in rats, but they did not markedly impair learning, as measured by the Morris water maze test. Injections of RRSA were found to trigger tau hyperphosphorylation in the rat hippocampus via GSK-3β activation. Tau hyperphosphorylation and GSK-3β activation were also observed in N2a cells in the presence of ribosylation-derived AGEs. Furthermore, the administration of ribosylation-derived AGEs induced the suppression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB). Both GSK-3β inhibition and BDNF treatment decreased the levels of phosphorylated tau in N2a cells. In particular, the administration of BDNF could rescue memory failure in ribosylated AGE-injected rats. Ribosylation-derived AGEs downregulated the BDNF-TrkB pathway in rat brains and N2a cells, leading to GSK-3β activation-mediated tau hyperphosphorylation, which was involved in the observed rat memory loss. Targeting ribosylation may be a promising therapeutic strategy to prevent Alzheimer's disease and diabetic encephalopathies.

Keywords: Advanced glycation end products; GSK-3β oxidative stress; brain-derived neurotrophic factor; ribosylation; tau hyperphosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / metabolism
  • Flow Cytometry
  • Glycation End Products, Advanced / metabolism*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Male
  • Maze Learning
  • Phosphorylation
  • Protein Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • tau Proteins / metabolism*

Substances

  • Glycation End Products, Advanced
  • tau Proteins
  • Protein Kinases
  • Glycogen Synthase Kinase 3 beta
  • tropomyosin kinase