Nrf2 Reduces Levels of Phosphorylated Tau Protein by Inducing Autophagy Adaptor Protein NDP52

Nat Commun. 2014 Mar 25;5:3496. doi: 10.1038/ncomms4496.

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor in the defence against oxidative stress. Here we provide evidence that activation of the Nrf2 pathway reduces the levels of phosphorylated tau by induction of an autophagy adaptor protein NDP52 (also known as CALCOCO2) in neurons. The expression of NDP52, which we show has three antioxidant response elements (AREs) in its promoter region, is strongly induced by Nrf2, and its overexpression facilitates clearance of phosphorylated tau in the presence of an autophagy stimulator. In Nrf2-knockout mice, phosphorylated and sarkosyl-insoluble tau accumulates in the brains concurrent with decreased levels of NDP52. Moreover, NDP52 associates with phosphorylated tau from brain cortical samples of Alzheimer disease cases, and the amount of phosphorylated tau in sarkosyl-insoluble fractions is inversely proportional to that of NDP52. These results suggest that NDP52 plays a key role in autophagy-mediated degradation of phosphorylated tau in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Animals
  • Autophagy*
  • Brain / metabolism*
  • Cerebral Cortex / metabolism
  • Female
  • HEK293 Cells
  • Hippocampus / metabolism
  • Humans
  • Maf Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oxidative Stress
  • Phosphorylation
  • RNA, Messenger / metabolism*
  • Rats
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • tau Proteins / metabolism*

Substances

  • CALCOCO2 protein, human
  • Maf Transcription Factors
  • NDP52 protein, mouse
  • NF-E2-Related Factor 2
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • tau Proteins