Changes with Age in the Activities of β-Secretase and the Aβ-Degrading Enzymes Neprilysin, Insulin-Degrading Enzyme and Angiotensin-Converting Enzyme

We recently found that insoluble A beta increases, but soluble A beta decreases with age in normal brains. We now report the changes in activities of beta-secretase (BACE-1) and A beta-degrading enzymes with age, and their relationships to concentrations of soluble and insoluble A beta. We measured BACE-1 activity and the levels and activities of neprilysin (NEP), insulin-degrading enzyme (IDE) and angiotensin-converting enzyme (ACE) in normal control brains (16 years-95 years). We also compared the measurements to those in AD. BACE-1 activity correlated closely with age in controls and was significantly higher in AD. In controls, NEP and IDE activities (but not protein levels) increased with age but ACE activity and level did not. BACE-1 activity correlated directly with insoluble but inversely with soluble A beta. IDE activity correlated directly with insoluble A beta and NEP activity was inversely related to soluble A beta. ACE level correlated directly with insoluble and inversely with soluble A beta in controls but not AD. Both A beta-synthesizing and -degrading enzyme activities increase with age, coinciding with declining soluble A beta and increasing insoluble A beta. Further research is needed to establish whether these changes in enzyme activity and A beta levels are causally related and if so how.