Tau protein aggregation is the most common pathology among neurodegenerative diseases, which collectively are termed “tauopathies.” These diseases encompass over 15 distinct disorders that greatly affect Veterans, including Alzheimer's disease (AD) and traumatic brain injury. As the most common cause of dementia in the United States, AD affects more than 5 million Americans, including 600,000 military personnel and costs $200 billion per year. Effective treatment strategies remain elusive. We are applying fresh perspectives from different disciplines and are investigating cellular senescence as a novel cell stress response involved in tau-associated neurodegeneration. Large insoluble tau-containing aggregates, neurofibrillary tangles (NFTs), are the closest histopathological correlate with neuron loss and cognitive decline in AD. However, because NFT-containing neurons do not die, their role in neurodegeneration remains unclear. We suggest that NFTs may evoke toxicity through secondary, non-cell autonomous mechanisms. Specifically, we propose that NFT-containing cells may contribute to tissue destruction by secreting toxic soluble factors in a mechanism similar to cellular senescence. Cellular senescence is generally characterized by a permanent cell cycle arrest and alterations in gene expression, metabolic state, morphology, and cytokine secretion. In neurons, “senescence” has been used to describe age-associated changes that include swelling of the soma, loss of dendritic spines, and progressive “choking of cytoplasmic space” with abnormal material; phenotypes in good agreement with NFT-containing neurons. While there is no single unifying marker that defines the complex senescence stress response, robust phenotypes include elevated gene expression of tumor suppressor p16INK4a (p16) and inflammatory cytokines. Studies have illustrated that senescent cells contribute to tissue damage and functional decline with age. Recently, we found that transgenic mice with NFTs have a significant elevation in senescence markers in the brain, including p16. The increase in p16 was associated with an elevation in brain cytokines, Tnfα and Il1β. Only mice with NFTs, but not age-matched controls with high levels of soluble tau, expressed senescence- associated factors. Collectively, these data suggest that pathogenic tau and cellular senescence are interconnected. The research goal is to elucidate whether tau-associated pathogenesis induces a senescence- like phenotype that reciprocally contributes to brain pathology and behavioral deficits in tau-associated neurodegenerative diseases. Ongoing studies with transgenic mice will focus on molecular mediators of cellular senescence in the brain, specific cell types involved and the mechanistic interplay among cellular senescence, tau pathology, neurodegeneration and cognitive decline. Through the activities proposed in this CDA-2, I will achieve my ultimate career goal: to become an independent investigator dedi...