Development of a novel viral vector-based model of dementia with Lewy bodies in mice

Preclinical research into dementia with Lewy bodies (DLB) is challenging due to the lack of α-synucleinopathy animal models that do not also develop Parkinsonism. To address this issue, we have developed a new mouse model for investigating the impact of α-synuclein (α-Syn) overexpression and aggregation on driving cortical and hippocampal circuit dysfunction. Using bilateral stereotaxic injections of adeno-associated virus (AAVs) vectors, we transduced overexpression of human SNCA (encoding α-Syn) with mScarlet (red fluorophore), or an mScarlet-only control vector. We targeted either dorsal hippocampus or primary visual cortex of both CX3CR1-GFP (microglial reporter) and hSNCA (homozygous knockout for mouse SNCA & knock-in for wildtype human SNCA) mice. We used immunohistochemistry to assess changes in neural circuitry at 6-, 8-, 16-, and 24-weeks post-injection. We detected human α-Syn in dorsal hippocampus after a 6-week incubation period, yet significant neurodegeneration was not observed despite widespread hippocampal α-Syn expression. However, following a 16-week period of incubation, a significant reduction in the thickness of CA1 stratum pyramidale was observed in hippocampus. Pilot data on neuronal cell loss, assessed through NeuN (neuron-specific marker) labelling, and microglial activation-induced neuroinflammation will be presented. These initial experiments have established a compelling proof of concept for our approach. Our ongoing investigation will determine whether α-Syn overexpression in the hippocampus induces spatial memory deficits after 6 months of SNCA overexpression. We aim to demonstrate efficacy of our model as a new translational tool, advancing our understanding of this intricate and multifaceted neurodegenerative disorder.