Using 6OHDA and aSyn PFFs to explore the role of tau mediated loss of synaptic dysfunction leading to cognitive dysfunction in Parkinson's disease

Abstract

Purpose: Parkinson's disease is the second most common form of neurodegenerative disease. Many PD patients will go on to develop Parkinson's disease dementia. Tau and a‐synuclein (aSyn) are implicated in dementia but the relationship between the two proteins is poorly understood. Using a 6‐hydroxydopamine model of PD, we investigated the role of tau in synapse loss, degeneration of the frontal cortex, hippocampal regions and cognitive dysfunction. Secondly, using a model in which aSyn preformed fibrils (PFFs) are injected into the brain, we explored the changes in tau proteins, synaptic markers, and behaviour that result from widespread aSyn pathology. Methods: 6OHDA/PFFs were stereotactically injected into the medial forebrain bundle (MFB) of rats and behaviour was examined defined time points. Immumohistochemical and biochemical techniques were used to detect tau and aSyn, synaptic markers and markers of oxidative stress. Results: The 6OHDA model showed visuospatial deficits and mild changes in post‐synaptic markers. Tau and aSyn phosphorylation were increased within the frontal cortex and hippocampus. In the aSyn PFF model we saw spread of aSyn pathology, accompanied by tau phosphorylation. There was a lack of overt behavioural phenotype, however, phosphorylated tau accumulated at synapses with, alterations to synaptic markers. Conclusion: Our data support an association between tau and aSyn phosphorylation in two models of PD. In the PFF model, accumulation of phosphorylated tau at synapses may account for alterations in synaptic markers. Oxidative stress markers are being examined to determine if oxidative stress is linked with the accumulation of pathological proteins and behavioural alterations in these PD models.