Age-dependent remodeling of the sciatic proteome in 5xFAD mice can be attenuated by exercise or donepezil treatment to maintain neuromuscular function.

Background: Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline and clinical diagnosis. Preclinical AD is associated with neuromuscular dysfunction. We previously characterized early neuromuscular impairment prior to cognitive decline at 4 months of age in the 5xFAD mouse model of AD. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood, therefore limiting interventional capacity. We hypothesized that either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Methods: Sciatic nerves from 5xFAD and wild-type (WT) mice were analyzed by tandem mass tag (TMT)-labeled proteomics at 3, 4, and 7 months to investigate proteome remodeling. Separate cohorts, using 3-month-old 5xFAD mice and WT littermates given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil to test if neuromuscular dysfunction could be attenuated. Afterwards, we assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in-vivo at 4 months. Additionally, we performed TMT-labeled proteomics to ascertain the effect of exercise and donepezil treatments on sciatic proteome. Results: Sciatic nerves in 5xFAD mice exhibited proteomic remodeling from 3 to 4 months, particularly in pathways linked to mitochondrial turnover, calcium handling, lipid metabolism, and inflammation, coinciding with onset of neuromuscular dysfunction. Both exercise and donepezil attenuated in nerve-stimulated muscle torque and CNAP dysfunction. Both exercise and donepezil attenuated proteomic remodeling of the sciatic nerve involving mitochondrial-centric processes through both shared and independent mechanisms. Conclusions: Declines in neuromuscular function may be pre-clinical identifiers for AD that share pathway similarities with noted central effects of the pathology on the brain. Our findings highlight the importance of a systemic approach to AD pathology and importance of disease state in interventional efficacy. Graphical abstract: Created in Biorender.