Mitochondriomics reveals the underlying neuroprotective mechanism of TrkB receptor agonist R13 in the 5×FAD mice

Neuropharmacology. 2022 Feb 15:204:108899. doi: 10.1016/j.neuropharm.2021.108899. Epub 2021 Nov 25.

Abstract

Decreased energy metabolism and mitochondrial biogenesis defects are implicated in the pathogenesis of Alzheimer's disease (AD). In present study, mitochondriomics analysis revealed significant effects of R13, a prodrug of 7,8-dihydroxyflavone, on mitochondrial protein expression profile, including the proteins related to the biological processes: fatty acid beta-oxidation, fatty acid metabolic process, mitochondrial electron transport, and mitochondrial respiratory chain. Cluster analysis demonstrated that R13 promoted mitochondrial oxidative phosphorylation (OXPHOS). The functional analysis showed that R13 increased ATP levels and enhanced OXPHOS including complex Ⅰ, Ⅱ, Ⅲ and Ⅳ. R13 treatment increased mitochondrial biogenesis by regulating the levels of p-AMPKα, p-CREB, PGC-1α, NRF1 and TFAM as a consequence of activation of TrkB receptor in the 5 × FAD mice. Finally, R13 significantly reduced the levels of tau phosphorylation and Aβ plaque. Our data suggest that R13 may be used for treating AD via enhancing mitochondrial biogenesis and metabolism.

Keywords: Alzheimer's disease; Mitochondrial biogenesis; OXPHOS; Proteomics; TrkB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / etiology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Electron Transport
  • Energy Metabolism* / drug effects
  • Fatty Acids / metabolism
  • Flavanones / pharmacology*
  • Flavanones / therapeutic use
  • Male
  • Mice, Transgenic
  • Mitochondria / genetics*
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism*
  • Molecular Targeted Therapy
  • Organelle Biogenesis*
  • Oxidation-Reduction
  • Phosphorylation / drug effects
  • Prodrugs / pharmacology*
  • Prodrugs / therapeutic use
  • Receptor, trkB / agonists*
  • Receptor, trkB / metabolism*
  • Transcriptome / genetics*
  • tau Proteins / metabolism

Substances

  • 7,8-dihydroxyflavanone
  • Amyloid beta-Peptides
  • Fatty Acids
  • Flavanones
  • Mitochondrial Proteins
  • Prodrugs
  • tau Proteins
  • Adenosine Triphosphate
  • Receptor, trkB