Mitochondrial Complex I as a Target for Neuroprotection in AD

Alzheimer’s Disease (AD) has no effective treatments, and recent clinical trials focused on preventing of amy- loid beta (Aβ) production have consistently failed. Alternative approaches are urgently needed. We identified mitochondrial complex I (MCI) as a small molecule druggable target for AD. Partial inhibition of MCI induced multifaceted adaptive stress response activating neuroprotective mechanisms in multiple familial mouse mod- els of AD. Chronic treatment with MCI inhibitors was efficacious after the onset of cognitive dysfunction, reduc- ing inflammation, oxidative stress, Aβ and pTau, leading to improved synaptic function, brain energetics, and cognitive performance, ultimately blocking the ongoing neurodegeneration. Translational potential was sup- ported by cross-validation of the mouse data with the human transcriptomic data from the NIH AMP-AD data- base, demonstrating that pathways improved by the treatment in AD mice, including the immune system re- sponse and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients. While mounting data suggest that the induction of mild energetic stress via MCI inhibition could promote longevity, increase health span, and delay the onset of age-related neurodegenerative disease, including AD, the mecha- nistic understanding of what makes targeting of MCI with small molecules safe is lacking. It is also remains to be determined whether this treatment could be beneficial in patients with late onset AD (LOAD), the most prev- alent form of the disease. The objective of this competitive renewal is to conduct structure-activity relationship studies using isolated mam- malian MCI, and array of biochemistry and cell biology techniques, reporter cells and human neurons, and a library of novel and established MCI inhibitors to determine what factors, including the site of MCI inhibition, binding affinity, levels and sites of ROS production, and the structure of small molecules ensure safety of MCI inhibition and the induction of a neuroprotective signaling. We will next validate efficacy of novel MCI inhibitor developed and patented in the lab in 3D co-cultures of neurons/astrocytes/microglia derived from the iPSCs of LOAD male and female patients. Finally, therapeutic efficacy and molecular mechanisms will be confirmed in APOE4 Knock In mouse model of LOAD. Cross-validation of multi-omics data with the existing human metabolic, epigenetic and transcriptomic databases will determine specific mechanisms reversed by the treatment in male and female LOAD patients, supporting translational value of this innovative therapeutic approach. Novel infor- mation delineating MCI as a small molecule druggable therapeutic target generated using isolated mammalian MCI, and advanced techniques, including cryo-EM, could significantly advance the field of drug discovery for AD and other diseases. Mechanistic studies using human and animal models of LOAD could provide novel evidence for the cell-specific role mitochondrial adaptive stress response plays in neuroprotection. Translational bi- omarkers of therapeutic efficacy could aid in the design of future clinical trials.