Tau Oligomers as a Potential Target for Treatment of Parkinson's Disease

Objective/Rationale:
Tau pathology is a prominent feature of synucleinopathies, such as Parkinson disease (PD) and dementia with Lewy Bodies (DLB). An emerging view in neurodegeneration is that visible tau aggregates such as neurofibrillary tangles (NFT) themselves are not toxic; rather, aggregates of a size intermediate between monomer and NFT so-called tau oligomers are pathogenic. In this project we will characterize tau oligomers in PD and DLB brain samples, their relation to synuclein oligomers and their role in neurorodegeneration.
Project Description:
Tau oligomers are the most toxic tau species and represent a potential drug target to combat neurodegeneration. We have recently developed a novel tau oligomers specific monoclonal antibody (TOMA) that recognizes only the toxic oligomeric form of tau, but not the normal non pathologic monomeric form or NFT. In this project we will use TOMA in combination with other antibodies to determine whether tau oligomers accumulate and co-localize with synuclein oligomers. TOMA enables us, for the first time, to analyze tau oligomers pathology and its role in the clinical scores despite the presence of a large amount of monomeric functional tau protein and pathologically irrelevant large tau structures. Sporadic PD and DLP human brain tissues and age-matched controls will be analyzed using immunehistochemical and biochemical methods.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The synergy between synuclein and tau in PD is not well understood. We hypothesize that synuclein oligomers cause tau aggregation and oligomerization leading to neurodegeneration. This project is critical for our understanding of the disease mechanism and progression. Moreover, the validation of tau oligomers as novel therapeutic target will be useful for the development of biomarkers and the evaluation of therapeutic methods and agents designed to decrease or eliminate tau oligomers neurotoxicity in PD.
Anticipated Outcome:
This project should yield novel insights into the interplay between alpha-synuclein and tau in the pathogenesis of PD and DLB and the role of tau oligomers in the disease progression; moreover, this project may validate tau oligomers as a potential target for a disease-modifying therapy for these diseases.