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ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

Florent Letronne1, Geoffroy Laumet1, Anne-Marie Ayral1

  • 1INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.

Ebiomedicine
|June 23, 2016
PubMed

Insights

Decreased ADAM30 expression may promote amyloid-beta (Aβ) production, contributing to Alzheimer's disease. This study reveals ADAM30's role in regulating amyloid precursor protein (APP) metabolism and Aβ levels.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Several metalloproteases (ADAMs) influence amyloid precursor protein (APP) metabolism.
  • The complete set of metalloproteases in APP metabolism is not fully understood.
  • Alzheimer's disease (AD) is characterized by amyloid plaque accumulation.

Purpose of the Study:

  • To investigate the role of ADAM30 in APP metabolism and its potential link to Alzheimer's disease.
  • To determine how ADAM30 expression levels affect amyloid-beta (Aβ) peptide production.

Main Methods:

  • Transcriptomic analysis of metalloprotease genes in AD brains.
  • In vitro studies involving down-regulation and up-regulation of ADAM30 expression.
  • Proteomics and cell-based assays to elucidate ADAM30's mechanism of action.
  • Experiments in Alzheimer-like transgenic mice.

Main Results:

  • AD brains showed a 50% decrease in ADAM30 expression, inversely correlating with amyloid load.
  • Altering ADAM30 expression modulated Aβ peptide levels in vitro.
  • ADAM30-dependent APP metabolism requires cathepsin D (CTSD) activation and lysosomal sorting.
  • Over-expression of ADAM30 in transgenic mice reduced Aβ42 secretion, amyloid plaque load, and improved cognitive function.

Conclusions:

  • Reduced ADAM30 expression may contribute to Alzheimer's disease by increasing Aβ production.
  • ADAM30 plays a crucial role in regulating APP metabolism through CTSD activation and lysosomal pathways.
  • Modulating ADAM30 activity presents a potential therapeutic strategy for Alzheimer's disease.
Keywords:
ADAM30APPAlzheimerAmyloidLTPMetabolism

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