The induction of the mitochondrial morphofunctional pathways improves bioenergetics in Alzheimer Disease

Alzheimer Disease (AD) currently has no effective treatments. A consistent failure of recent clinical trials focused on Aβ or pTau protein accumulation necessitates the identification of novel therapeutic targets and strategies. The loss of cellular energetics is considered as an underlying dysfunction in AD. We have identified small molecule compounds that partially inhibit mitochondrial complex I (MCI), blocking neurodegeneration via the induction of multiple neuroprotective mechanisms, including the improvement of cellular energy homeostasis in vitro and in vivo in multiple AD models. Mitochondria are highly motile organelles that respond to physiologic cues through the dynamic properties of mitochondrial networks, which are balanced by the flux of fusion and fission events. This study aims to demonstrate that treatment with partial MCI inhibitors improves cellular energetics and function via modulation of mitochondrial dynamics using multiple models, including neuronal cells generated from human iPSCs derived from ApoE4+ late‐onset AD (LOAD) patients and ApoE3+ controls.