The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the predominant \u03b2-secretase, cleaving the amyloid precursor protein (APP) via the amyloidogenic pathway. In addition, BACE1 as an amyloid degrading enzyme (ADE), cleaves A\u03b2 to produce the C-terminally truncated non-toxic A\u03b2 fragment A\u03b234 which is an indicator of amyloid clearance. Here, we analyzed the effects of BACE1 inhibitors on its opposing enzymatic functions, i.e., amyloidogenic (A\u03b2 producing) and amyloidolytic (A\u03b2 degrading) activities, using cell culture models with varying BACE1\/APP ratios. Under high-level BACE1 expression, low-dose inhibition unexpectedly yielded a two-fold increase in A\u03b242 and A\u03b240 levels. The concomitant decrease in A\u03b234 and secreted APP\u03b2 levels suggested that the elevated A\u03b242 and A\u03b240 levels were due to the attenuated A\u03b2 degrading activity of BACE1. Notably, the amyloidolytic activity of BACE1 was impeded at lower BACE1 inhibitor concentrations compared to its amyloidogenic activity, thereby suggesting that the A\u03b2 degrading activity of BACE1 was more sensitive to inhibition than its A\u03b2 producing activity. Under endogenous BACE1 and APP levels, \u00ab\u00a0low-dose\u00a0\u00bb BACE1 inhibition affected both the A\u03b2 producing and degrading activities of BACE1, i.e., significantly increased A\u03b242\/A\u03b240 ratio and decreased A\u03b234 levels, respectively. Further, we incubated recombinant BACE1 with synthetic A\u03b2 peptides and found that BACE1 has a higher affinity for A\u03b2 substrates over APP. In summary, our results suggest that stimulating BACE1’s ADE activity and halting A\u03b2 production without decreasing A\u03b2 clearance could still be a promising therapeutic approach with new, yet to be developed, BACE1 modulators.<\/p>\n","protected":false},"author":14,"featured_media":0,"template":"","meta":{"_acf_changed":false},"studies-relation":[],"class_list":["post-12018","ccna_publication","type-ccna_publication","status-publish","hentry"],"acf":[],"yoast_head":"\n