The Effects of Treadmill Exercise in the P301S Mouse Model of Tau Pathology

Tauopathies are a group of neurodegenerative disorders characterized by severe cognitive and motor deficits that are associated with the development of neurofibrillary tangles (NFTs), intracellular protein aggregates composed of hyperphosphorylated tau (a microtubule associated protein). The accumulation of NFTs (along with senile plaques) is one of the neuropathological hallmarks of Alzheimer's disease (AD), and there is evidence that NFT accumulation is positively correlated with the severity of AD symptoms (Arriagada et al., 1992; Ghoshal et al., 2002; Mitchell et al., 2002). Current FDA-approved pharmacological treatments do not alter AD progression and only temporarily alleviate symptoms. However, recent evidence suggests that physical exercise may slow the progression of AD and other tauopathies. The following dissertation project investigated the impact of treadmill exercise in a transgenic mouse model of neurodegenerative tauopathy. The central hypothesis was that endurance treadmill exercise would slow the development of neurodegenerative tau pathology and associated behavioral impairments in the P301S-tau transgenic mouse model of tauopathy. Old (7-month old) and young (3-month old) P301S mice were subjected to 12- and 24-weeks of exercise, respectively. Following exercise, mice were given behavioral assessments. Immunohistochemical and biochemical analysis was also performed to assess the impact of exercise on behavior and pathology. When old P301S mice with advanced tau pathology where introduced to treadmill exercise for 12 weeks: 1) enhanced exploratory locomotion, 2) a decrease in pathological tau hyperphosphorylation and 3) reduction of aggregated (insoluble) tau, which was confirmation of the central hypothesis. When young P301S without advanced pathology where introduced to treadmill exercise for 24 weeks, the following changes were observed: 1) reduced hyperactivity, 2) enhanced muscular strength, 3) restoration of normal anxiety-like behavior, 3) improved associative memory 4) a decrease in pathological tau hyperphosphorylation and 5) reduction of aggregated (insoluble) tau, which also confirmed the central hypothesis. Despite the numerous benefits of this exercise regimen before and after the onset of significant tau pathology and behavioral dysfunction, exercise had no impact on cell loss. Additionally, it was observed that the majority of changes associated with therapeutic exercise occurred in the spinal cord, whereas preventative exercise appeared to have greater benefits in the brain. These observations offer insight on the impact of consistent and regular exercise in tau-related dementias. Moreover, these observations add to the growing body of literature on the importance of incorporating physical activity into a healthy lifestyle, to help combat the onset and progression of dementia.