Partial Mitochondrial Complex I Inhibitors as a Therapy for Alzheimer Disease

Mechanistic studies revealed that C458 and C273 activate a mitochondrial stress response, augmenting mitochondrial biogenesis, antioxidant signaling, and autophagy, which collectively provided protection against Aβ toxicity in multiple in vitro and in vivo models of AD. These findings demonstrate that weak mtCI inhibition by novel compounds C458 and C273, with improved drug-like properties, is neuroprotective. This supports the feasibility of developing safe and efficacious mtCI inhibitors as a disease-modifying strategy for AD.