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

ABSTRACT: INTRODUCTION:There is keen interest in elucidating the biological mechanisms underlying recent failures of ?-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 ? (A?). DISCUSSION:Elevation of BACE1 by 7 of 8 BACE1 inhibitors raises new concerns about advancing such ?-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? by dissociating ?/? secretase complexes are better candidates because they neither inhibit ?- and ?-secretase nor increase BACE1 levels.

SUBMITTER: Liu L 

PROVIDER: S-EPMC6756967 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature