Mitochondrial complex Ⅰ as a therapeutic target for Alzheimer's disease

• 作者: Eugenia Trushina Sergey Trushin Md Fayad Hasan
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2022,（2）
• 所属期刊栏目: Special Column: Drug target and drug development for Alzheimer's disease
• 页码范围: 483-495
• 页数: 13页
• 语种: 英文

摘要

Alzheimer's disease(AD),the most prominent form of dementia in the elderly,has no cure.Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials.Novel therapeutic targets and strategies are urgently needed.Emerging data sug-gest that in response to environmental stress,mitochondria initiate an integrated stress response(ISR)shown to be beneficial for healthy aging and neuroprotection.Here,we review data that implicate mito-chondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR.Specifically,partial inhi-bition of mitochondrial complex Ⅰ has been exploited as a novel strategy for multiple human conditions,including AD,with several small molecules being tested in clinical trials.We discuss current understand-ing of the molecular mechanisms involved in this counterintuitive approach.Since this strategy has also been shown to enhance health and life span,the development of safe and efficacious complex Ⅰ inhibitors could promote healthy aging,delaying the onset of age-related neurodegenerative diseases.