Investigating spreading of alpha--synuclein and the consequences on cognitive dysfunction and neuropathology in experimental Parkinson’s disease models.

Abstract

Objective: Approximately 50% of PD patients will develop Parkinson’s disease dementia (PDD). Neuropathologically PDD is characterized by Lewy Bodies and Lewy neurites that are present throughout the brain. LBs and LNs are comprised primarily of a-synuclein (aSyn) aggregates but the role of these aggregates in neurodegeneration is not fully understood. The goal of our study is to investigate the consequences of aSyn aggregation and spread on neurodegeneration and cognition in different models of experimental PD. Methods: The medial forebrain bundle (MFB) of Sprague Dawley rats was injected with either 6-hydroxydopamine (6OHDA) or aSyn preformed fibrils (PFFs). Behavioral tests were used to measure resulting motor and cognitive deficits. Phosphorylation of tau, aSyn, presence of oxidative stress and neuronal loss was assessed by biochemical and immunohistochemical methods in brain regions connected to the MFB. Results: 6OHDA triggered motor deficits and cognitive deficits indicated by increased latency in Morris water maze test in 3 weeks. Concomitant with these abnormalities were increased phosphorylated tau and aSyn in several brain regions. PFF-injected rats showed only spreading of phosphorylated aggregates of aSyn in the absence of associated motor or cognitive deficits within 120 days. Conclusion: 6OHDA injection into MFB promotes the phosphorylation of tau and aSyn, motor and cognitive dysfunction and neurodegeneration. However, spread of aSyn PFFs from the site of injection was insufficient to trigger deficits in motor or cognition skills. These data suggest that accumulation of phospho-aSyn alone may not be sufficient to induce dementia associated with neurodegeneration in the cerebral cortex and hippocampus.