Aug 17, 2019

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

Alzheimer's & Dementia : the Journal of the Alzheimer's Association
Lei LiuDennis J Selkoe


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. 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. 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). 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.

  • References32
  • Citations1


Mentioned in this Paper

Transcription, Genetic
Alzheimer's Disease
Induced Pluripotent Stem Cells
BACE1 protein, human
Immunoassay Method
Clinical Trials
Compound (Substance)

Related Feeds

Alzheimer's Disease: Early Markers

Alzheimer's disease is a chronic neurodegenerative disease. This feed focuses on early markers, as well as environmental, pharmacological, and drug-response biomarkers associated with this disease.

Alzheimer's Disease: APP

Amyloid precursor protein proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques. Here is the latest research.

Alzheimer's Disease: Transcription

Transcription involves copying (transcribing) the gene's DNA sequence into RNA. Impaired transcription is associated with the pathogenesis and progression of conditions such as Alzheimer's disease (AD). Here are the latest discoveries pertaining to transcription and this disease.

Alzheimer's Disease: Neuroimaging

Alzheimer's disease (AD) is a chronic neurodegenerative disease. Here is the latest research on neuroimaging modalities, including magnetic resonance imaging and positron emission tomography, in AD.

Alzheimer's Disease: RNA Sequencing

RNA sequencing is used to reveal the presence and quantity of RNA in a given sample. In this feed, RNA sequencing investigates the genetic and molecular mechanisms related to the pathophysiology of Alzheimer's disease (AD). Here are the latest discoveries pertaining to RNA sequencing and this disease.

Alzheimer's Disease: Genetics

Alzheimer's disease is a chronic neurodegenerative disease. Discover genetic and epigenetic aspects of Alzheimer’s disease, including genetic markers and genomic structural variations here.