Overview of Alzheimer's Disease Associated with Hsp90 and Its Co-Chaperone Network

Alzheimer's disease has been a serious threat to global health, especially with the aging population. In 2021, around 57 million people worldwide were living with dementia, and 60-70% of these cases were attributed to AD. Dementia is the seventh leading cause of death and a major contributor to disability and care dependency among aging adults. Dementia accounted for US$1.3 trillion in global economic costs in 2019. AD has two histopathological hallmarks: extracellular β-amyloid plaques and intracellular neurofibrillary tangles made up of hyperphosphorylated tau. Despite decades of intensive research, approved drugs have collectively failed to show sufficient clinical efficacy. Hsp90 is an ATP-dependent molecular chaperone and plays a dual role in AD, depending on the co-chaperone with which it associates. Since Hsp90 serves a dual function in AD and most Hsp90 inhibitors lack specificity for a given Hsp90 paralogue, these complexities pose major challenges for therapeutic development. This review outlines the dual role of Hsp90 and its co-chaperone network in AD, with a focus on four key co-chaperones. We also discuss two chaperone-targeting drugs and their mechanisms of action.