Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer's disease cognition.

ABSTRACT:

Background

The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer's disease (AD) besides age itself, but the mechanisms underlying this risk are debated. One hypothesis supported by evidence from multiple labs is that apoE4 binds to the amyloid-β (Aβ) peptide and catalyzes its polymerization into neurotoxic oligomers and fibrils. Inhibiting this early step in the amyloid cascade may thereby reduce or prevent neurodegeneration and AD.

Methods

Using a design of experiments (DOE) approach, we developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of Aβ into oligomers and fibrils. We used it to screen the NIH Clinical Collection of small molecule drugs tested previously in human clinical trials. We then evalu

SUBMITTER: Johnson NR 

PROVIDER: S-EPMC9241285 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature