R01AG075809

Using a Novel MTBI Model to Investigate Phosphorylation Dependent Common Mechanisms in Tauopathies

Alzheimer's Disease (AD) and many related dementias (ADRDs) are tauopathies, characterized by somatodendritic accumulation of tau and intraneuronal inclusion bodies composed of tau species that have undergone extensive post-translational modification. Although some disease-specific tau modifications have been identified, many are conserved across the full range of tauopathies. We do not yet have a deep understanding of the molecular processes that generate these tau protein modifications, or of their functional consequences in promoting pathogenic cascades. This knowledge gap is a major contributor to our current inability to generate effective therapeutic interventions for AD and other tauopathies.

The central hypothesis we are testing here is that a range of pathogenic events induce phosphorylation of tau at specific residues, resulting in mislocalization of tau within the cell and subsequent synaptic dysfunctions. We believe that inhibition of these early tau phosphorylation events will in turn inhibit tau pathologies and associated signaling deficits. This hypothesis is based on our published work, primarily utilizing cultured cell experimental systems. The direct relevance of this mechanism to human disease is further supported by the recent finding that phosphorylation of tau at these same specific residues is an early event preceding tau fibril formation in AD disease progression.

Our overall objective here is to test and further refine this hypothesis in a novel mouse model we have developed (MAPT-GR) that expresses all isoforms of human tau at physiologic levels and ratios. We have found that mild traumatic brain injury (MTBI) induces a rapid phosphorylation and somatodendritic mislocalization of human tau in these mice. Importantly, we can prevent this tau mislocalization by inhibiting phosphorylation.

The specific aims of this study are as follows:

1. Determine the dynamic changes in the subcellular distribution of phosphorylated tau. We will utilize our novel tauopathy model to test the working hypothesis that phosphorylation of tau at specific residues leads to somatodendritic accumulation of tau, tau mislocalization to dendritic spines, and alters micro-components of dendritic spines.

2. Determine the synaptic and circuit dysfunctions associated with the phosphorylation of tau. We will test the working hypothesis that mislocalization of phosphorylated tau to somatodendritic domains and dendritic spines results in synaptic and circuit dysfunction in our model.

3. Identify the impact of inhibiting these early phosphorylation events on tau mislocalization and associated signaling deficits. We will test our working hypothesis that MTBI activates GSK3β and CDK5, which phosphorylate the B and C domain of the tau protein.

Expected Outcomes: We expect to identify the early-stage pathologies and dysfunctions caused by phosphorylation of tau and provide proof-of-concept demonstrations of the extent to which these dysfunctions can be prevented by blocking tau phosphorylation at specific residues. Of equal importance, we expect to have optimized a model and experimental platform in which potential therapeutic compounds that target this common disease mechanism can be tested and optimized.

Regents Of The University Of Minnesota

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Minneapolis, Minnesota 554553008 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 298% from $767,250 to $3,053,656.