Wednesday, April 24, 2024
4/24/2024
Currently, there are no drugs that halt the progression of Alzheimer's disease (AD). This constitutes an important problem because >5 million people in the United Sates are affected. The deposition of Tau fibrils throughout the brain is a pathological hallmark of the disease. Targeting the fibrils holds promise for therapeutic intervention. MAP2 is a protein that is highly homologous to Tau and is found in close proximity to Tau deposits. The objective of this proposal is to determine how MAP2 modulates Tau fibril formation. The central hypothesis is that MAP2 caps Tau fibrils at the ends and thereby inhibits fibril growth. This hypothesis has been formulated based on data produced in the applicant's laboratory that reveals specific interactions between Tau fibrils and MAP2. The rationale is that once the modulatory roles of MAP2 are resolved, new strategies can be developed that utilize MAP2 as a blocking agent of Tau fibril formation. Supported by strong preliminary data the central hypothesis will be tested by pursuit of the following three specific aims. 1) Evaluate the inhibitory effects of MAP2 on the elongation of AD-derived Tau fibrils. 2) Identify the molecular mechanism of MAP2-mediated inhibition. 3) Determine how MAP2 modulates the propagation of distinct Tau fibril conformers. The research is innovative because it establishes an endogeneous protein with high sequence homology to Tau as a potent new inhibitor of Tau fibrillization. The proposed research is significant because it is expected to lead to new strategies for the prevention and treatment of a wide range of Tau misfolding diseases including AD. The research is exploratory and lays the foundation for future studies into the phenotypic diversity of human Tauopathies and novel therapeutic approaches that utilize homology-based inhibition of Tau fibrillization.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
