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 β-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 β (Aβ).

Discussion

Elevation of BACE1 by 7 of 8

SUBMITTER: Liu L 

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

REPOSITORIES: biostudies-literature