Isaac W. Babcock, United States of America
Colorado State University Department of Biochemistry and Molecular BiologyAuthor Of 1 Presentation
ALPHA-SYNUCLEIN INDUCES COFILIN PATHOLOGY: IMPLICATIONS FOR PARKINSON’S DISEASE DEMENTIA
Abstract
Aims
Besides the typical motor symptoms, dementia is recognized as a major complication in Parkinson’s disease (PD). PD-dementia appears to be associated with the accumulation of alpha-synuclein (aSyn) in the hippocampus. Cofilin-actin rods are neuropathology-related structures which have been implicated in synaptic dysfunction and cognitive impairment mainly in Alzheimer’s disease (AD). Here, we investigated whether hippocampal cofilin pathology impacts on cognitive dysfunction and dementia in PD.
Methods
Cofilin pathology was studied in vitro by the overexpression of aSyn or exogenous addition of aSyn pre-formed fribils (PFFs), in primary cultures of hippocampal neurons and in cultured hippocampal slices. Additionally, rod formation was evaluated in a PD mouse model overexpressing human aSyn in neurons (Thy1-aSyn mice) and presenting cognitive dysfunction, and in post mortem hippocampal sections from PD patients with cognitive impairment and dementia.
Results
Our in vitro results showed that elevated levels of aSyn induce cofilin-actin rods in hippocampal neurons, impacting on dendritic spine number and morphology, through a mechanism involving PrPC and NADPH oxidase pathways. Importantly cofilin pathology was validated in the hippocampus of Thy1-aSyn mice, at the same age where cognitive impairment is observed, and in hippocampal sections from PD patients with dementia.
Conclusions
This work proposes the innovative hypothesis that hippocampal cofilin pathology underlies synaptic impairment and cognitive dysfunction in PD. Currently, we are further exploring in vivo the consequences of cofilin pathology, and of its modulation using rod inhibitors, on synaptic dysfunction and cognitive impairment using the Thy1-aSyn mice. This will contribute to establish cofilin-actin rods as a novel therapeutic target for dementia in PD.