Multiple BACE1 inhibitors abnormally increase the BACE1 protein level in neurons by prolonging its half-life

Introduction: There is keen interest in elucidating the biological mechanisms underlying recent failures of beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1) inhibitors in Alzheimer's disease trials. Methods: We developed a highly sensitive and specific immunoassay for BACE1 in cell lines and iPSC-derived human neurons to systematically analyze the effects of eight clinically relevant BACE1 inhibitors. Results: Seven of 8 inhibitors elevated BACE1 protein levels. Among protease inhibitors tested, the elevation was specific to BACE1 inhibitors. The inhibitors did not increase BACE1 transcription but extended the protein's half-life. BACE1 became elevated at concentrations below the IC50 for amyloid beta(A beta). Discussion: Elevation of BACE1 by 7 of 8 BACE1 inhibitors raises new concerns about advancing such beta-secretase inhibitors for AD. Chronic elevation could lead to intermittently uninhibited BACE1 when orally dosed inhibitors reach trough levels, abnormally increasing substrate processing. Compounds such as roburic acid that lower A beta by dissociating beta/gamma secretase complexes are better candidates because they neither inhibit beta- and gamma-secretase nor increase BACE1 levels. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.