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

Abstract

We recently found that insoluble Abeta increases, but soluble Abeta decreases with age in normal brains. We now report the changes in activities of beta-secretase (BACE-1) and Abeta-degrading enzymes with age, and their relationships to concentrations of soluble and insoluble Abeta. 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 Abeta. IDE activity correlated directly with insoluble Abeta and NEP activity was inversely related to soluble Abeta. ACE level correlated directly with insoluble and inversely with soluble Abeta in controls but not AD. Both Abeta-synthesizing and -degrading enzyme activities increase with age, coinciding with declining soluble Abeta and increasing insoluble Abeta. Further research is needed to establish whether these changes in enzyme activity and Abeta levels are causally related and if so how.

Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex

“…Age was significantly higher in the hypertensive cohort. Demographic and neuropathological data for this cohort are summarised in Table 3. ACE, IDE and NEP protein and activity in these cases had been previously measured and published [30,31,[33][34][35][36]41]. ACE protein had been measured using the ACE Duoset ELISA kit (R&D systems) and ACE activity had been measured using the ACE1-specific fluorogenic substrate Abz-FRK(Dnp)-P (Biomol International, Exeter, UK) in the presence of captopril (1 mM) in brain homogenates prepared in 1% SDS lysis buffer, as detailed in Miners et al [35,36].…”

Effect of Tong Luo Jiu Nao on Aβ-degrading enzymes in AD rat brains

“…An increasing number of strategies for treating AD are aimed at promoting the clearance of A␤ in the brain (Miners et al, 2008;Bates et al, 2009;Deane et al, 2009;Buoso et al, 2010;Kasturirangan and Sierks, 2010). A␤ is produced continuously and its concentration is determined in part by the activities of several degradative enzymes, including neprilysin (NEP), insulindegrading enzyme (IDE), endothelin-converting enzyme (ECE), angiotensin-converting enzyme (ACE), and plasmin (Carson and Turner, 2002;Miners et al, 2008Miners et al, , 2010. A decrease in the activity of any of these enzymes due to genetic mutation or age-or disease-related alterations in gene expression or proteolytic activity may increase the risk for AD (Yoshida et al, 2005).…”

Transcriptional Regulation of Insulin-degrading Enzyme Modulates Mitochondrial Amyloid β (Aβ) Peptide Catabolism and Functionality

“…By using in vitro degradation assays with synthetic peptides as substrates, significantly lower activity of hPreP isolated from temporal lobes of the brains of AD cases and of transgenic mice as models of AD was recently reported (10), suggesting a crucial role of PreP in the clearance of mitochondrial A␤ (mitA␤) (11). In regard to expression and activity of cytosolic IDE in AD brains, there are still controversies with reports showing decrements (12)(13)(14)(15), increments (16,17), or no changes (18,19). It has been proposed that part of the loss of IDE and PreP activities in AD brain may be due to oxidative damage to which both proteases are highly sensitive (7,20).…”