Endothelin-converting enzymes and related metalloproteases in Alzheimer's disease

The efficient clearance of Amyloid-β (Aβ) is essential to modulate levels of the peptide in the brain and to prevent it from accumulating in senile plaques, a hallmark of Alzheimer's disease (AD) pathology.We and Others have shown that failure in Aβ catabolism can produce elevations in Aβ concentration similar to those observed in familial forms of AD. Based on the available evidence, it remains plausible that in late-onset AD, disturbances in the activity of Aβ degrading Enzymes could induce Aβ accumulation, and that this increase could result in AD pathology. The following review presents a historical perspective of the parallel discovery of three vasopeptidases (Neprilysin and endothelin-converting enzymes-1 and -2) as important Aβ degrading Enzymes. The recognition of the role of these vasopeptidases in Aβ degradation, beyond bringing to light a possible explanation of how cardiovascular risk factors may influence AD risk, highlights a possible risk of the use of inhibitors of these Enzymes for Other clinical indications such as hypertension. We will discuss in detail the experiments conducted to assess the impact of vasopeptidase deficiency (through pharmacological inhibition or genetic mutation) on Aβ accumulation, as well as the cooperative effect of multiple Aβ degrading Enzymes to regulate the concentration of the peptide at multiple sites, both intracellular and extracellular, throughout the brain.