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Multiple BACE1 Inhibitors Abnormally Increase the BACE1 Protein Level in Neurons by Prolonging Its Half-Life

Multiple BACE1 Inhibitors Abnormally Increase the BACE1 Protein Level in Neurons by Prolonging Its Half-Life

Lei Liu, Bianca M Lauro, Li Ding, Matteo Rovere, Michael S Wolfe, Dennis J Selkoe

Alzheimers Dement. 2019 Sep;15(9):1183-1194.

PMID: 31416794

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 BACE1 inhibitors raises new concerns about advancing such β-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 Aβ by dissociating β/γ secretase complexes are better candidates because they neither inhibit β- and γ-secretase nor increase BACE1 levels.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP6812813	Roburic acid		6812-81-3	Price

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