TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production

Nat Commun. 2015 Nov 19:6:8876. doi: 10.1038/ncomms9876.

Abstract

Generation of β-amyloid (Aβ) peptide in Alzheimer's disease involves cleavage of amyloid precursor protein (APP) by γ-secretase, a protease known to cleave several substrates, including Notch. Finding specific modulators for γ-secretase could be a potential avenue to treat the disease. Here, we report that transient receptor potential canonical (TRPC) 6 specifically interacts with APP leading to inhibition of its cleavage by γ-secretase and reduction in Aβ production. TRPC6 interacts with APP (C99), but not with Notch, and prevents C99 interaction with presenilin 1 (PS1). A fusion peptide derived from TRPC6 also reduces Aβ levels without effect on Notch cleavage. Crossing APP/PS1 mice with TRPC6 transgenic mice leads to a marked reduction in both plaque load and Aβ levels, and improvement in structural and behavioural impairment. Thus, TRPC6 specifically modulates γ-secretase cleavage of APP and preventing APP (C99) interaction with PS1 via TRPC6 could be a novel strategy to reduce Aβ formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Protein Binding
  • TRPC Cation Channels / genetics
  • TRPC Cation Channels / metabolism*
  • TRPC6 Cation Channel

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Presenilin-1
  • TRPC Cation Channels
  • TRPC6 Cation Channel
  • TRPC6 protein, human
  • Amyloid Precursor Protein Secretases