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

Abstract

AbstractBackgroundAlzheimer 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.MethodChanges in protein expression in response to treatment were assessed using the Western Blot analysis. The investigation of mitochondrial morphology was done using electron microscopy. Flow cytometry was used to measure the translocation of glucose transporters to the cell surface. Cellular energetics was assessed using a Seahorse Extracellular Flux Analyzer. Results were validated in 3xTgAD mice.ResultWe found that the 2D culture of LOAD cultures had accumulation of pTau and a significant reduction in the expression of proteins involved in mitochondrial dynamics and function, including mitochondrial preprotein translocase TIM23, mitochondrial transcription factor A, transcription factor FoxO3, and mitochondrial fusion proteins MFN2 and OPA1. Treatment with partial MCI inhibitors improved mitochondrial dynamics, rescuing the expression of MFN2 and OPA1, neuronal bioenergetics, and mitochondrial morphology. MCI inhibitors increased surface translocation of GLUTs enhancing glucose uptake and utilization, which could be measured in 3xTgAD mice in vivo using translational biomarker FDG‐PET.ConclusionMild stress caused by the application of MCI inhibitors induced mitochondrial fusion, improved energy homeostasis, and enhanced glucose uptake and utilization in vitro and in vivo. These findings could be instrumental for the validation of a novel medicinal approach and the development of biomarkers for therapeutic efficacy.