Advanced age is the greatest risk factor for most chronic diseases, yet pathogenic mechanisms tend to be highly tissue specific. In brain, intraneuronal inclusions of tau protein are the most common pathology. Collectively referred to as ?tauopathies,? these diseases encompass over 15 distinct disorders, including Alzheimer's disease. During pathogenesis, neurons accumulate hyperphosphorylated tau, soluble tau oligomers and eventually large insoluble neurofibrillary tangles (NFTs). NFTs are the closest histopathological correlate with neuron loss and cognitive decline in AD, but the neurons with NFTs do not die. Thus, the contribution of NFTs to AD pathophysiology remains unknown. The role of NFTs in evoking toxicity through secondary, non-cell autonomous mechanisms has not been explored. Using a well-characterized mouse model of tauopathy, we recently found evidence of the involvement of one such pathway: cellular senescence. When this cell stress response becomes chronically activated, the affected cell acquires apoptosis resistance and begins secreting soluble factors that are toxic to neighboring cells. 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. This K01 will be conducted at the Barshop Institute at the University of Texas Health Science Center in San Antonio under the mentorship of Dr. Nicolas Musi, co-mentorship of Drs. Veronica Galvan, Paul Hasty and George Perry, and Advisory Counsel of Drs. Judith Campisi, Karen Ashe and Bradley Hyman. I propose to combine a tauopathy mouse model with technology to in vivo track and ablate senescent cells. This highly innovative system will be complemented with precise stereological brain assessment and classical histological, biochemical and cellular measures to identify the pathogenic and cellular source of senescence. Moreover, functional outcomes will be elucidated through animal frailty measures and behavioral experiments. The planned activities coupled with formal and informal interactions with members of the Mentoring and Advisory committee will ensure the proposed career development and scientific goals are achieved. By the completion of the K01 I will be (1) fully prepared to lead an independent biology of aging research program focused on AD; (2) have generated sufficient data to compete for R01 funding; (3) and negotiated tenure-track faculty advancement.

K01AG056671

2017-09-01

2022-05-31