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Multiple BACE1 inhibitors abnormally increase the BACE1 protein level in neurons by prolonging its half‐life
Author(s) -
Liu Lei,
Lauro Bianca M.,
Ding Li,
Rovere Matteo,
Wolfe Michael S.,
Selkoe Dennis J.
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.3918
Subject(s) - amyloid precursor protein secretase , amyloid precursor protein , enzyme , protease , bace1 as , chemistry , pharmacology , biochemistry , disease , biology , medicine , alzheimer's disease
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 IC 50 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.