Re-entry Supplement associated with R01AG08073

PROJECT SUMMARY During early stages of Alzheimer’s Disease (AD), skeletal muscle mass and function precipitously declines in comparison to those who are cognitively intact, potentially due to poor neuromuscular health. Thus, bioenergetics of peripheral tissues may have an underappreciated role in AD etiology. Exercise is an effective means to promote mitochondrial and neuromuscular health. However, whether regular exercise has therapeutic potential for delaying or preventing AD is an outstanding question. Thus far, we have shown in 5xFAD mice, a model of AD, neuromuscular dysfunction is present at a young age before observable cognitive decline and that muscle mitochondrial respiration does not improve following 12 weeks exercise training in 22-week-old 5xFAD mice compared to WT. In sum, impaired neuromuscular function may underlie a maladaptive bioenergetic response to exercise prior to overt manifestation of AD-like pathology. There is a critical need therefore to define adaptive neuromuscular mechanisms in relation to established neuropathological changes over the continuum of AD-like pathology to identify novel therapeutic targets. To that end, we generated preliminary data demonstrating that treatment with the acetylcholinesterase inhibitor Donepezil before neuromuscular impairment, was sufficient to delay onset of declines in nerve-stimulated muscle torque and compound sciatic nerve action potential (CNAP) in 5xFAD mice. Thus, our central hypothesis is that combining DPZ with exercise training will normalize the adaptive response of skeletal muscle to exercise, improving mitochondrial quality through delay of AD-related neuromuscular degeneration. We propose one aim: Aim 1) Determine neuromuscular adaptive response to endurance exercise training in AD mice before AD-like pathology. 1a. To investigate the influence of DPZ on mitochondrial quality following endurance exercise training I will assess mitochondrial respiration, reactive oxygen species (ROS) production (via Oroboros O2K), as well as synthesis (i.e. biogenesis) and breakdown (via D2O labeling - GC/MS) of muscle mitochondria in 5xFAD male and female mice following 12 weeks voluntary wheel running with or without DPZ in comparison to sedentary controls. 1b. To assess the combined impact of exercise and DPZ on neuromuscular function I will assess pre- and post-exercise training and DPZ treatment muscle function in vivo (Aurora), exercise capacity and substrate utilization (CLAMs), body composition (NMR), NMJ integrity (histology and confocal microscopy) and compound nerve action potential (CNAP) of sciatic nerve. This supplement will bolster and expand upon the associated funded award (R01AG057825) by introducing a clinically employed pharmaceutical treatment (Donepezil). Anticipated discoveries are anticipated to further the development of targeted translational strategies related to novel identification of risk, as well as prevention and treatment of AD.