α-Synuclein Fibril Seeding Model (Limbic System)
Injection of α-synuclein PFFs into the Anterior Olfactory Nucleus (AON) to generate a Parkinson's disease mouse model with altered sleep, brain atrophy, and neuroinflammation.
Synuclein Model Overview
For this Parkinson's disease model, we perform stereotaxic inoculation of recombinant preformed fibrils (PFFs) into the Anterior Olfactory Nucleus (AON) of M83 mice [B6;C3-Tg( Prnp SNCA A53T )83Vle/J]. The rationale for targeting the AON includes:
- It is one of the earliest sites to demonstrate alpha-synuclein (α-synuclein; α-syn) pathology (Lewy bodies) in human Parkinson's disease (Braak Stage 1)
- Non-motor symptoms associated with the limbic system (e.g. hyposmia/anosmia, sleep alterations) are prevalent, early symptoms of Parkinson's disease (PD)
- The AON is connected to several ipsilateral & contralateral brain regions, including direct (1st order) connections to olfactory bulb, amygdala, piriform cortex, and higher order connections, such as the entorhinal cortex and hippocampus; many of these regions are highly vulnerable to neurodegeneration
Spatial pattern of spread of α-synuclein pathology in this animal model of Parkinson's disease following stereotaxic injection of recombinant preformed fibrils into the anterior olfactory nucleus (AON) of M83 transgenic mice.
A significant advantage of this rodent model is that it reproduces many aspects of human Parkinson's disease, including:
- Highly reproducible spreading of α-synuclein in a well-defined spatiotemporal pattern, resulting in extensive α-synuclein pathology in neuronal cell bodies and neurites
- Strong neuroinflammation (microgliosis and astrogliosis)
- Neurodegeneration & regional brain atrophy
- Measurable behavioral changes, such as alterations of sleep/wake cycles
- Amenable to disease modification via therapeutic intervention
Synuclein Model Generation
A general schema for synuclein PFF animal model generation is:
We have in-licensed the M83 transgenic (tg) mice which show α-syn overexpression. As a Preclinical Neuroscience CRO, we maintain a well-established breeding colony of these transgenic alpha-synuclein mice in-house at Biospective, allowing us to conduct large-scale (>100 mice) studies.
For this specific rodent model, we breed and age M83+/- male mice to 8-12 weeks-of-age. We then perform stereotaxic injection of sonicated, recombinant human alpha-syn PFFs into the AON. We use digital stereotaxic devices with automated microinjectors for high accuracy & precision.
This animal model is highly reproducible with a nearly 100% success rate of synuclein PFF seeding.
Our Synuclein Mouse Model Validated Measures
- Body weight
- Clinical scores
- Sleep analysis
- MRI brain atrophy (Read More in our Presentation - Brain atrophy analysis in rodent models of neurodegenerative diseases)
- FDG PET imaging of cerebral glucose hypometabolism
- Neurofilament Light measures in plasma & CSF
- Immunohistochemistry & multiplex immunofluorescence (Read More in our Presentation - Microglial activation in an α-synuclein mouse model of Parkinson's disease)
Phosphorylated alpha-synuclein immunohistochemistry staining of the ipsilateral (left) and contralateral (right) piriform cortex at 12 weeks post-injection following unilateral stereotaxic inoculation of alpha-synuclein preformed fibrils (PFFs) into the anterior olfactory nucleus of an M83+/- transgenic mouse.
Learn more about our characterization of this model, our validated measures, and our Preclinical Neuroscience CRO services.
Discover more of our Parkinson's Disease Models
Yes. We see highly elevated levels of neurofilament light in the plasma and CSF of the alpha-synuclein fibril seeding mice.
We also observe highly significant brain atrophy of multiple regions, such as the piriform cortex and entorhinal cortex, via in vivo MRI (see Brain atrophy analysis in rodent models of neurodegenerative diseases).