RT Journal Article
SR Electronic
T1 Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.28.437389
DO 10.1101/2021.03.28.437389
A1 Noah R. Johnson
A1 Athena C.-J. Wang
A1 Christina Coughlan
A1 Stefan Sillau
A1 Esteban Lucero
A1 Lisa Viltz
A1 Neil Markham
A1 Cody Allen
A1 A. Ranjitha Dhanasekaran
A1 Heidi J. Chial
A1 Huntington Potter
YR 2021
UL http://biorxiv.org/content/early/2021/03/29/2021.03.28.437389.abstract
AB The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer’s disease (AD) besides age itself, but the mechanism(s) underlying this risk are debated. The critical test of any proposed AD mechanism is whether it leads to effective treatments. We developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of the amyloid β (Aβ) peptide into neurotoxic fibrils. Screening a human drug library, we identified five non-toxic, blood-brain-barrier-permeable hit compounds that reduced apoE4-promoted Aβ and tau neuropathology in cultured neurons. Two hit compounds, imipramine and olanzapine, but not other (non-hit) antipsychotics or antidepressants, when prescribed to AD patients for their normal clinical indications, led to improvements in cognition and clinical diagnosis. Imipramine and olanzapine have no structural, functional, or clinical similarities other than their ability to inhibit apoE4-catalyzed Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD.One Sentence Summary High-throughput drug screens, studies in Alzheimer’s disease cell culture models, and analyses of human clinical data identified inhibitors of the apoE4-Aβ interaction as a novel class of Alzheimer’s disease therapeutics.Competing Interest StatementThe authors have declared no competing interest.