Neprilysin and amyloid beta peptide degradation

Abstract

Neprilysin is a zinc metalloendopeptidase with relatively broad substrate specificity. The enzyme is localized to the plasma membrane of cells where it can function to degrade extracellular peptides. Structural studies show that neprilysin preferentially cleaves peptides on the amino side of hydrophobic amino acids. Neprilysin has been implicated in the catabolism of amyloid beta peptides in the brain and as such has received considerable attention, particularly as a therapeutic target for Alzheimer's disease. An inverse relationship between neprilysin levels and amyloid beta peptide levels and between neprilysin levels and amyloid plaque formation has been observed in human brain. Neprilysin levels decline with aging in the temporal and frontal cortex possibly contributing to higher amyloid beta peptide levels. A number of studies have shown that increasing neprilysin levels in the brain leads to a decrease in brain amyloid beta peptide levels. Most recently a potential relationship between amyloid beta peptide synthesis from the amyloid precursor protein and neprilysin activity has been proposed.