Neuro-immune Interactions | 2020
Co-Pathologies Drive Neuroinflammation and Progression in PD
Study Rationale: While Parkinson’s disease (PD) is considered a synucleinopathy, the clinical progression of PD is driven by additional pathological proteins such as tau and beta amyloid. Team Kordower’s overarching hypothesis argues that these pathologies, in concert, result in brain inflammation that may be different in character and/or quantity than single pathology states.
Hypothesis: Team Kordower will test the hypothesis that the induction of co-pathologies will provide more construct and face validity in the context of human disease, and thus be a superior model for the evaluation of future novel therapies.
Study Design: Herein Team Kordower proposes to create novel nonhuman primate models of co-pathology and inflammation through treatment with alpha synuclein preformed fibrils, AAV-tau, and beta amyloid via aging and transgenesis. Team Kordower will validate these models by comparing their findings to inflammatory processes seen in human brain samples and refine exploration of the mechanisms involved by blocking these pathologies in mice and nonhuman primates using specific immunotherapies.
Impact on Diagnosis/Treatment of Parkinson’s Disease: The failure to have discovered disease modified treatments for PD may in large part be due to the failure to create relevant animal models to test novel therapeutic strategies. Clearly single pathology models do not reflect the multiple pathologies seen in PD. The mouse and nonhuman primate models to be created and validated in this application along with a deep understanding of their downstream inflammatory pathways will provide essential platforms for testing novel therapeutic strategies.
Team Kordower's program will study the influence of co-pathologies that occur in PD, such as tau and beta amyloid, in inflammation and disease progression to guide future combinatorial therapeutic efforts. View Team Outcomes.
Here is an overview of how this team’s article findings have contributed to the PD field as of November 2023. There are two different categorizations of these contributions – one by impact to the PD community and a second by scientific theme.
Is Tau the initial pathology in dopaminergic nigrostriatal degeneration? Studies in Parkinsonism and Parkinson’s disease
Parkinson’s disease features a variety of pathologies. However, the order in which those pathologies appear and how they contribute to neurodegeneration is unclear. In this report, Team Kordower analyzed patients with mild motor deficits and found that initiation of neurodegeneration occurs independently of alpha-synuclein aggregation and may be mediated by the protein tau.
Members of the team have been recognized for their contributions.
- 2023 Collaborative Meeting: Jhodi Webster, Community Poster Prize Winner; San Diego
Other Team Activities
- Working Groups:
- PFF Gut-Brain – Laura Volpicelli-Daley (Co-Chair)
- Trainee – Jhodi Webster (Co-Chair)
- Interest Groups: PD Modeling – Rodent & Fly Models – Ashley Harms (Co-Chair)