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 (ADAM30mut) 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.
Highlights • By transcriptomic analyses, low levels of ADAM30 expression was observed in the brain of AD cases (compared with controls). • Activation of cathepsin D by ADAM30 is required to modulate the APP metabolism in vitro, i.e. decrease in Ab secretion. • In AD-like mice, neuronal ADAM30 expression led to lower soluble Aβ42, amyloid plaques and to rescue long term potentiation The amyloid precursor protein (APP) processing is central in the etiology of Alzheimer's disease (AD). Characterizing the actors of this metabolism is thus an important challenge. We searched for proteins involved in the APP processing and we selected the A disintegrin-like and metalloprotease 30 (ADAM30). Our results revealed an axis in APP metabolism pathway through an ADAM30-dependent cathepsin D activation. When activated following ADAM30 expression, a decrease in Aβ secretion occurred in vitro and in vivo. ADAM30 under-expression observed in AD brains and thus the impairment of the ADAM30-dependent pathway may favor Aβ peptide production and, ultimately, AD development.