PMID- 35768831 OWN - NLM STAT- MEDLINE DCOM- 20220701 LR - 20230601 IS - 1758-9193 (Electronic) VI - 14 IP - 1 DP - 2022 Jun 29 TI - Imipramine and olanzapine block apoE4-catalyzed polymerization of Abeta and show evidence of improving Alzheimer's disease cognition. PG - 88 LID - 10.1186/s13195-022-01020-9 [doi] LID - 88 AB - BACKGROUND: The apolipoprotein E (APOE) epsilon4 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-beta (Abeta) 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 Abeta 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 evaluated the efficacy and cytotoxicity of the hit compounds in primary neuron models of apoE4-induced Abeta and phosphorylated tau aggregation. Finally, we performed retrospective analyses of the National Alzheimer's Coordinating Center (NACC) clinical dataset, using Cox regression and Cox proportional hazards models to determine if the use of two FDA-approved hit compounds was associated with better cognitive scores (Mini-Mental State Exam), or improved AD clinical diagnosis, when compared with other medications of the same clinical indication. RESULTS: Our high-throughput screen identified eight blood-brain barrier (BBB)-permeable hit compounds that reduced apoE4-catalyzed Abeta oligomer and fibril formation in a dose-dependent manner. Five hit compounds were non-toxic toward cultured neurons and also reduced apoE4-promoted Abeta and tau neuropathology in a dose-dependent manner. Three of the five compounds were determined to be specific inhibitors of apoE4, whereas the other two compounds were Abeta or tau aggregation inhibitors. When prescribed to AD patients for their normal clinical indications, two of the apoE4 inhibitors, imipramine and olanzapine, but not other (non-hit) antipsychotic or antidepressant medications, were associated with improvements in cognition and clinical diagnosis, especially among APOE4 carriers. CONCLUSIONS: The critical test of any proposed AD mechanism is whether it leads to effective treatments. Our high-throughput screen identified two promising FDA-approved drugs, imipramine and olanzapine, which have no structural, functional, or clinical similarities other than their shared ability to inhibit apoE4-catalyzed Abeta polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD. CI - (c) 2022. The Author(s). FAU - Johnson, Noah R AU - Johnson NR AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Wang, Athena C-J AU - Wang AC AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Coughlan, Christina AU - Coughlan C AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Sillau, Stefan AU - Sillau S AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Lucero, Esteban AU - Lucero E AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Viltz, Lisa AU - Viltz L AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Markham, Neil AU - Markham N AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Allen, Cody AU - Allen C AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Dhanasekaran, A Ranjitha AU - Dhanasekaran AR AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Chial, Heidi J AU - Chial HJ AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. FAU - Potter, Huntington AU - Potter H AD - Department of Neurology, University of Colorado Alzheimer's and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. huntington.potter@cuanschutz.edu. LA - eng GR - P30 AG049638/AG/NIA NIH HHS/United States GR - P50 AG016573/AG/NIA NIH HHS/United States GR - P50 AG005133/AG/NIA NIH HHS/United States GR - P50 AG005136/AG/NIA NIH HHS/United States GR - P30 AG019610/AG/NIA NIH HHS/United States GR - R01 AG037942/AG/NIA NIH HHS/United States GR - P30 AG010161/AG/NIA NIH HHS/United States GR - P30 AG062428/AG/NIA NIH HHS/United States GR - P30 AG035982/AG/NIA NIH HHS/United States GR - P30 AG013854/AG/NIA NIH HHS/United States GR - P30 AG053760/AG/NIA NIH HHS/United States GR - P30 AG010129/AG/NIA NIH HHS/United States GR - P30 AG072946/AG/NIA NIH HHS/United States GR - P30 AG062429/AG/NIA NIH HHS/United States GR - P30 AG010124/AG/NIA NIH HHS/United States GR - P30 AG010133/AG/NIA NIH HHS/United States GR - P30 AG062421/AG/NIA NIH HHS/United States GR - P50 AG005146/AG/NIA NIH HHS/United States GR - U01 AG016976/AG/NIA NIH HHS/United States GR - P50 AG047266/AG/NIA NIH HHS/United States GR - F99 NS115330/NS/NINDS NIH HHS/United States GR - P30 AG062422/AG/NIA NIH HHS/United States GR - P30 AG008051/AG/NIA NIH HHS/United States GR - P50 AG023501/AG/NIA NIH HHS/United States GR - P50 AG005681/AG/NIA NIH HHS/United States GR - K23 AG031861/AG/NIA NIH HHS/United States GR - P30 AG028383/AG/NIA NIH HHS/United States GR - P50 AG008702/AG/NIA NIH HHS/United States GR - P50 AG047270/AG/NIA NIH HHS/United States GR - P50 AG005138/AG/NIA NIH HHS/United States GR - P50 AG005142/AG/NIA NIH HHS/United States GR - P30 AG008017/AG/NIA NIH HHS/United States GR - P30 AG072947/AG/NIA NIH HHS/United States GR - P30 AG062715/AG/NIA NIH HHS/United States GR - P50 AG047366/AG/NIA NIH HHS/United States GR - P50 AG025688/AG/NIA NIH HHS/United States GR - P30 AG013846/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20220629 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 0 (Amyloid beta-Peptides) RN - 0 (Apolipoprotein E4) RN - N7U69T4SZR (Olanzapine) RN - OGG85SX4E4 (Imipramine) SB - IM MH - *Alzheimer Disease/metabolism MH - Amyloid beta-Peptides/metabolism MH - *Apolipoprotein E4/genetics/metabolism MH - Catalysis MH - Cognition MH - Humans MH - Imipramine/therapeutic use MH - Olanzapine/therapeutic use MH - Polymerization MH - Retrospective Studies PMC - PMC9241285 OTO - NOTNLM OT - Amyloid-beta OT - Antidepressant OT - Antipsychotic OT - Apolipoprotein E OT - Dementia OT - High-throughput screening COIS- The authors declare that they have no competing interests. EDAT- 2022/06/30 06:00 MHDA- 2022/07/02 06:00 PMCR- 2022/06/29 CRDT- 2022/06/29 23:42 PHST- 2022/03/07 00:00 [received] PHST- 2022/05/11 00:00 [accepted] PHST- 2022/06/29 23:42 [entrez] PHST- 2022/06/30 06:00 [pubmed] PHST- 2022/07/02 06:00 [medline] PHST- 2022/06/29 00:00 [pmc-release] AID - 10.1186/s13195-022-01020-9 [pii] AID - 1020 [pii] AID - 10.1186/s13195-022-01020-9 [doi] PST - epublish SO - Alzheimers Res Ther. 2022 Jun 29;14(1):88. doi: 10.1186/s13195-022-01020-9.