Dcf1 alleviates C99-mediated deficits in drosophila by reducing the cleavage of C99

Biochem Biophys Res Commun. 2020 Sep 17;530(2):410-417. doi: 10.1016/j.bbrc.2020.05.063. Epub 2020 Jun 12.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. The generation of amyloid-β from the amyloid precursor protein (APP) C-terminal fragment (C99) by γ-secretase cleavage is one of the main pathological mechanisms of AD. Dendritic cell factor 1 (Dcf1) is a membrane protein that was previously found to play a role in the development of AD. Bioinformatic analysis of AD patients indicated that Dcf1 may affect γ-secretase. In this study, we confirmed that Dcf1 attenuates the cleavage of C99 in vivo and in vitro. By using C99 transgenic AD drosophila, we found that Dcf1 reduces the cleavage of C99 by γ-secretase using Dcf1 overexpression. The climbing ability and lifespan of C99 drosophila were significantly increased, while learning and memory were also enhanced with Dcf1 expression. Increased levels of C99 protein in Dcf1-AD drosophila reveals inhibition of C99 cleavage by Dcf1 in vivo. Dcf1 inhibition of γ-secretase was further confirmed in vitro. These results provide a potential therapeutic target for the treatment of AD and also propose a new mechanism for understanding the occurrence of AD.

Keywords: Alzheimer’s disease; C99; Dcf1; Drosophila.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Drosophila* / genetics
  • Drosophila* / physiology
  • Humans
  • Longevity
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Memory
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Up-Regulation

Substances

  • Amyloid beta-Protein Precursor
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Recombinant Proteins
  • TMEM59 protein, human
  • amyloid beta-protein precursor C-terminal fragment beta, human
  • Amyloid Precursor Protein Secretases