  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.
