Aβ_31-35 Decreases Neprilysin-Mediated Alzheimer's Amyloid-β Peptide Degradation

Alzheimer's disease is associated with the deposition of extracellular senile plaques, made primarily of amyloid-β (Aβ), particularly peptides Aβ_1-42 and Aβ_1-40. Neprilysin, or neutral endopeptidase (NEP), catalyzes proteolysis of the amyloid peptides (Aβ) and is recognized as one of the major regulators of the levels of these peptides in the brain, preventing Aβ accumulation and plaque formation. Here, we used a combination of techniques to elucidate the mechanism of Aβ binding and cleavage by NEP. Our findings indicate that the Aβ_31- cleavage products remain bound to the neprilysin active site, reducing proteolytic activity. Interestingly, it was already shown that this Aβ_31-35 sequence is also critical for recognition of Aβ peptides by other targets, such as the serpin-enzyme complex receptor in neuronal cells.