Accelerated and Localized Synucleinopathy in a Hybrid Mouse Model: Implications for Positron Emission Tomography Studies

BACKGROUND: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by α-synuclein (α-syn) aggregation, dopamine (DA) neuron loss, and neuroinflammation. Synucleinopathy, the α-syn-related pathology, is the central to the pathogenetic processes observed in the brains of patients with PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). We are seeking an animal model with synucleinopathy that can comprehensively replicate these pathologies and adhere to suitable timeframes for preclinical research for positron emission tomography (PET) imaging studies. OBJECTIVE: To evaluate the synucleinopathy mouse model that closely replicates key pathological features through immunohistochemistry (IHC) and to assess the application of this model for PET studies. METHODS: An adeno-associated virus (AAV) carrying the mutated human α-syn gene (AAV1/2-CMV-human-A53T α-syn) and preformed fibrils (PFF) of mutated recombinant human α-syn (S87N) were co-injected into the left substantia nigra (SN) of mouse brains. PET/CT imaging and IHC were performed at different time points post-injection to detect the key pathologies in the brain. RESULTS: This model resulted in accelerated α-syn pathology, detectable as early as two weeks post-surgery, alongside DA neuron loss, microglial activation, reduced synaptic density, and impaired mitochondrial function within five weeks. The pathologies were localized, making the model suitable for PET imaging studies and/or PET ligand development. Both IHC and PET imaging confirmed the spatial relevance of these pathologies. CONCLUSIONS: This hybrid (AAV/PFF) mouse model provides an accelerated and localized platform for studying synucleinopathies such as PD, as well as for evaluating PET ligands for disease diagnosis and monitoring.