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

TL;DR

This study reveals that ADAM30 reduces amyloid-beta levels in Alzheimer's disease by activating cathepsin D and promoting APP lysosomal sorting, offering potential therapeutic insights.

Contribution

It demonstrates that ADAM30 downregulation is linked to increased amyloid load and shows that ADAM30 activation decreases Aβ peptides via cathepsin D activation and lysosomal APP processing.

Findings

ADAM30 expression inversely correlates with amyloid load in AD brains.

Overexpression of ADAM30 reduces Aβ42 secretion and plaque load in transgenic mice.

ADAM30 activates cathepsin D, promoting APP lysosomal degradation.

Abstract

Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amy-loid 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 A$\beta$ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30 mut) did not affect A$\beta$ 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 A$\beta$42 secretion in neuron primary cultures, soluble A$\beta$42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation.