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

EBioMedicine. 2016 Jul:9:278-292. doi: 10.1016/j.ebiom.2016.06.002. Epub 2016 Jun 2.


Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amyloid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down- or up-regulation of ADAM30 expression triggered an increase/decrease in Aβ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30(mut)) did not affect Aβ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered Aβ42 secretion in neuron primary cultures, soluble Aβ42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation alterations. Our data thus indicate that lowering ADAM30 expression may favor Aβ production, thereby contributing to Alzheimer's disease development.

Keywords: ADAM30; APP; Alzheimer; Amyloid; LTP; Metabolism.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors
  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amino Acid Sequence
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Cathepsin D / chemistry
  • Cathepsin D / metabolism*
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Lysosomes / metabolism
  • Macrolides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Patch-Clamp Techniques
  • Pepstatins / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism


  • Amyloid beta-Peptides
  • Macrolides
  • Pepstatins
  • RNA, Small Interfering
  • bafilomycin A
  • Cathepsin D
  • ADAM Proteins
  • ADAM30 protein, human
  • pepstatin