Sequential or simultaneous injection of preformed fibrils and AAV overexpression of alpha-synuclein are equipotent in producing relevant pathology and behavioral deficits
Abstract
Background: Preclinical rodent models for Parkinson's disease (PD) based on viral human alpha-synuclein (h-$\alpha$Syn) overexpression recapitulate some of the pathological hallmarks as it presents in humans, such as progressive cell loss and additional synucleinopathy in cortical and subcortical structures. Recent studies have combined viral vector-based overexpression of human wild-type $\alpha$Syn with the sequential or simultaneous inoculation of preformed fibrils (PFFs) derived from human $\alpha$Syn.
Objective: The goal of the study was to investigate whether sequential or combined delivery of the AAV vector and the PFFs are equipotent in inducing stable neurodegeneration and behavioral deficits.
Methods: Here we compare between four experimental paradigms (PFFs only, AAV-h-$\alpha$Syn only, AAV-h-$\alpha$Syn with simultaneous PFFs, and AAV-h-$\alpha$Syn with sequential PFFs) and their respective GFP control groups.
Results: We observed reduction of TH expression and loss of neurons in the midbrain in all AAV (h-$\alpha$Syn or GFP) injected groups, with or without additional PFFs inoculation. The overexpression of either h-$\alpha$Syn or GFP alone induced motor deficits and dysfunctional dopamine release/reuptake in electrochemical recordings in the ipsilateral striatum. However, we observed a substantial formation of insoluble h-␣Syn aggregates and inflammatory response only when h-$\alpha$Syn and PFFs were combined. Moreover, the presence of h-$\alpha$Syn induced higher axonal pathology compared to control groups.
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