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 evaluated the efficacy and cytotoxicity of the hit compounds in primary neuron models of apoE4-induced Aβ 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 Aβ oligomer and fibril formation in a dose-dependent manner. Five hit compounds were non-toxic toward cultured neurons and also reduced apoE4-promoted Aβ 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 Aβ 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 Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD.

Pinus halepensis Essential Oil Ameliorates Aβ1-42-Induced Brain Injury by Diminishing Anxiety, Oxidative Stress, and Neuroinflammation in Rats

“…The inhalation of PNO in both concentrations resulted in significant increases in the swimming time ( p = 0.0003 for 1% PNO and p = 0.0022 for 3% PNO) ( Figure 3 A) as well as significant reductions of the immobility time ( p = 0.0001 for 1% PNO and p = 0.0015 for 3% PNO) ( Figure 3 B). Imipramine (Imp), a tricyclic antidepressant, also assessed as a disease-modifying treatment for AD [ 89 ], has been used as a positive control within the FST.…”

Screening Techniques for Drug Discovery in Alzheimer’s Disease

“…In a study to identify small molecules that prevent the interaction between apoE4 and Aβ, ThT assay was used. 28 The assay was able to monitor Aβ fibrillization and study the catalytic effects of apoE4, then was optimized to be used in HTS and identify inhibitors of apoE4-Aβ interaction. A drug screen was conducted using 595 compounds from the NIH Clinical Collection (NCC) library, resulting in the identification of 134 hits.…”

“…In a study to identify small molecules that prevent the interaction between apoE4 and Aβ, ThT assay was used . The assay was able to monitor Aβ fibrillization and study the catalytic effects of apoE4, then was optimized to be used in HTS and identify inhibitors of apoE4-Aβ interaction.…”

Protein Interactome of Amyloid-β as a Therapeutic Target

“…Liu et al found that the inhibition of its interaction with Aβ using CPO-Aβ17–21 peptide led to a decrease in cognitive impairment and neuroprotection in an AD APP/PS1 transgenic mouse model [ 122 ]. Recent studies have shown that blocking the ability of APOE to initiate Aβ oligomerization also has a therapeutic effect—a similar approach has been successfully tested in imipramine and olanzapine preparations on 5xFAD transgenic mice, TgF344-AD transgenic rats, and a primary neuronal culture obtained from these animals [ 123 ].…”