Attenuation of Alzheimer’s Disease-Driven Memory Loss and Pain Behavior by Novel Isoform-Selective Heat Shock Protein 90-Beta Inhibitors

Abstract: Alzheimer’s Disease (AD) is the most common cause of dementia and impacts over 6 million people in the United States. Its incidence grows with age, and therapeutics are urgently needed to halt disabling neuropsychological symptoms impacting patients and their families, notably, insidious memory loss. However, people with dementia also experience distressing levels of pain, thus understanding mechanisms driving pain in dementia is critically important in their care. Pain is the most shared symptom by more than half of patients with varying levels of dementia in their final week of life and 77% of patients with dementia rely on opioids for pain relief.

Here, we report the reversive arm of our studies to modify tightly evolutionarily conserved molecular chaperone protein networks that are closely tied to systemic immunological processes by selectively inhibiting a specific isoform of Heat Shock Protein 90 (Hsp90) in transgenic 5xFAD mice. Non-selective pan-Hsp90 inhibitors are robustly effective in treating AD via anti-inflammatory immune modulation of microglia signaling but were halted in clinical use by toxic side effects. Studies suggest toxicity of pan-Hsp90 inhibitors is driven mostly by effects of Hsp90α inhibition. Our lead compound is >333 fold selective for Hsp90β over Hsp90α and can selectively inhibit Hsp90β while skirting Hsp90α inhibition, thus we predict being able to achieve similar benefits with fewer side effects. We hypothesized that selective Hsp90β inhibition will reduce AD pathology in the 5xFAD mouse model by immune modulation, specifically by decreasing inflammatory microglial activation, and report immunohistochemical findings here. In addition, our previous studies show that Hsp90β-selective inhibition enhances morphine pain relief, a salient opioid dose-reducing bonus in this patient population.