# 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.

## Key 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.

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Source: https://tomesphere.com/paper/1906.07511