The project proposed here has two objectives: to characterize an early marker in tau polymerization and to design and characterize a novel antibody to this particular early conformation. Preliminary evidence suggests that the assembly of paired helical filaments of tau is preceded by the formation of an oligomeric intermediate. The distinct assembly properties and morphology of this oligomeric intermediate will be further characterized using tau assembly assays that both directly and indirectly monitor assembly. Evidence suggests that while this oligomeric intermediate is more labile than filaments, it may persist long enough to serve as a marker for eventual tau accumulation and subsequent neuronal death. This oligomer will be used to synthesize a novel monoclonal antibody that is conformationally specific. Antibodies produced will be comprehensively screened, and ones that specifically recognize the oligomeric conformation of tau will be selected for further use in studies. The antibody has the potential for many therapeutic applications in the research of Alzheimer's Disease, and in design of therapies for Alzheimer's Disease and other neurodegenerative diseases with tau pathology. The antibody could be directly applied to ongoing studies using antibodies to detect levels of tau protein in cerebrospinal fluid of patients, and may assist in early diagnosis of patients by detecting the tau oligomeric conformation. Furthermore, pathological studies using this antibody may provide significant evidence towards identification of patients with early Alzheimer's Disease. Together, the aims of this study will facilitate a greater understanding of tau filaments and tau filament assembly in a number of neurodegenerative diseases including Alzheimer's Disease.
