P301L‐Tau Expression Induces Skeletal Muscle Abnormalities in Mouse Model of Tauopathy

Abstract

AbstractBackgroundPatients suffering from Alzheimer’s disease (AD) and related tauopathies often report signs of muscle weakness. The pathological accumulation of insoluble tau that forms neurofibrillary tangles (NFTs) is a hallmark of AD, yet it is unclear whether pathological tau impacts skeletal muscle. Proper muscle function is necessary for movement and consequently impacts quality of life in tauopathy patients, while concurrently contributing to the physiological maintenance of whole‐body endocrine and metabolic homeostasis. Skeletal muscle crosstalks with other organ systems; therefore, disruption of skeletal muscle health impacts whole‐body processes, such as the formation of pathological tau. The objective of this study was to determine the links between tauopathy and muscle function.MethodI performed intracerebroventricular injections with adeno‐associated viral (AAV) vector encoding P301L human tau (N = 4 females, 7 males) or a control plasmid (empty or a yellow fluorescent protein construct) (N = 5 females, 6 males). At 3 months, I measured grip strength. I harvested the brain, soleus, and tibialis anterior (TA) muscles at 15 months, and measured muscle mechanics concurrently in the soleus and extensor digitorum longus (EDL) muscles. I biochemically detected soluble tau and visualized TA structure immunohistochemically.ResultsGrip strength was reduced at 3 months in the P301L tau‐expressing mice of both sexes. The intrinsic force production of the soleus, but not the EDL, was reduced in P301L tau‐expressing males at 15 months. At this same time point, soluble tau accumulated in the cortex but not the soleus. Aggregation of nuclei were found histologically in the TA of P301L tau expressing mice but not in controls.ConclusionChanges in grip strength preceded insoluble tau accumulation and cognitive decline typical of this model. Reductions in the soleus force production indicate that P301L tau overexpression in the brain impacts intrinsic muscle strength, and occurs independently of innervation. The nuclear clumps detected in the TA of P301L tau‐expressing mice suggest that AAV‐P301L‐tau injections in the brain promote an inflammatory response in muscle. Together these data suggest that pathological tau species that are expressed in the brain reach peripheral tissues and exert deleterious consequences such as skeletal muscle abnormalities.