Chaperone Protein Modification as Dementia Treatment: Novel Heat Shock Protein 90-Beta Inhibitor Attenuates Cognitive Changes in Alzheimer’s Disease

Abstract

Alzheimer’s Disease is the most common cause of dementia and impacts over 6 million people in the United States. Age is the greatest risk factor in developing Alzheimer’s Disease, leading to an overwhelming projected amount of people impacted as the population ages. Despite an established history of research focused on targeting the amyloid beta plaques and neurofibrillary tangles that create its known pathological hallmarks, clinical trials of drugs specific to amyloid beta processing or removal have failed extensively with a few recent exceptions; thus, treatable targets underpinning Alzheimer’s Disease pathology remain elusive and are likely multi-faceted. Therapeutics are urgently needed to halt the disabling neuropsychological symptoms that impact patients and their families, particularly 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. In the context of widespread failed clinical trials and extraordinary economic waste and societal burden, modern studies of Alzheimer’s Disease therapeutics must acknowledge the remarkably complex interactions the immune system has with inflammation, injury, and cell signaling. Non-selective pan-Hsp90 inhibitors were robustly effective in treating Alzheimer’s Disease memory loss and pathology burden by way of anti-inflammatory immune modulation of microglia signaling but any potential for clinical use was halted over 20 years ago by severe side effects observed in toxicity studies. Later research suggested toxicity of pan-Hsp90 inhibitors was driven mostly by effects of Hsp90-alpha inhibition alone. Here, we endeavor to fully test the potential of Hsp90-beta inhibitor, NDNB-01, in the treatment of Alzheimer’s Disease using a transgenic 5xFAD Familial Alzheimer’s Disease mouse model. Six-month-old female and male 5xFAD mice were treated daily by subcutaneous injection of our highly selective Hsp90-beta inhibitor NDNB-01 (1mg/kg) for eight-to-nine weeks and tested with biweekly open field (OFT), novel object recognition (NOR), and overnight nestbuilding assays and additional Morris Water Maze (MWM), tail flick, Hargreaves, social motivation and social recognition memory, and Elevated Plus Maze (EPM) testing at other time points. Our previous pilot data in younger mice suggested Hsp90-beta inhibition conferred a cognitive benefit in long-term 7-day retention NOR testing at thirteen weeks of treatment and altered loss of thigmotaxis. In older 6-to-8-month-old mice, Hsp90-beta inhibition enhanced 24-hr spatial memory in MWM, ameliorated cognitive changes in OFT and EPM, improved nest-building, and trends toward restored thermal nociception and social motivation/memory behavior. Total distance traveled, speed, and other locomotor parameters were not modified by NDNB-01 treatment suggesting a cognition-specific effect over motor-specific effects. We hypothesize that selective Hsp90-beta inhibition will reduce AD pathology in the 5xFAD mouse model by immune modulation, specifically by decreasing inflammatory microglial activation, and report findings here. In addition, our previous studies show that Hsp90-beta-selective inhibition enhances morphine pain relief, a salient opioid dose-reducing bonus in this patient population who rely on opioids for pain relief in later stages of their life.