Specific Modulation of Tau Oligomers by Passive Immunotherapy in a Parkinson's Disease Model

Objective/Rationale: 
The accumulation of tau protein is an important pathogenic factor in Parkinson’s disease (PD) and other neurodegenerative disorders. Our recent findings from pre-clinical models and human brain tissues suggest that tau oligomers (comprised of two or more tau molecules) play a key role in eliciting Parkinson`s disease. In this project, we will target these toxic species via passive immunization.

Project Description: 
We have developed a novel anti-tau oligomer-specific monoclonal antibody (TOMA). This antibody does not recognize the soluble, functional monomeric tau or mature tau tangles. In this project, we will specifically target tau oligomer by passive immunotherapeutic approaches using an alpha-synuclein pre-clinical model of PD. We will perform two studies: reversal and prevention. In the reversal study, TOMA will be administered intravenously to aged models, and its effects on the PD-like phenotypes will be assessed by multiple approaches. In the prevention study, young models will receive biweekly TOMA injections for six months. During this period the models will be evaluated side-by –side with control models that will receive biweekly injections of non- specific antibody. After the final behavioral evaluation, models will be systematically analyzed.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Recently, tau-based immunotherapeutic approaches have emerged as a potential treatment for Alzheimer`s disease. This project is expected to establish tau oligomers critical role in PD pathogenesis and may validate tau oligomers as a potential target for a disease-modifying immunotherapy, either alone or in combination with anti-alpha-synuclein immunotherapeutic approaches.

Anticipated Outcome:          
In the prevention study, we anticipate that TOMA will prevent the disease progression in the synuclein PD pre-clinical models as they age. Moreover, we expect the TOMA will reverse the phenotypes in aged models. Finally, we expect that TOMA will reduce tau oligomers and perhaps alpha-synuclein oligomers in immunized models. We do not expect to see reduction in total tau and alpha-synuclein, and most likely TOMA treatment will not affect the insoluble tau and alpha-synuclein fibrillar aggregates.