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:
![Parkinson's Disease - Synuclein PFF injection AON process](https://bspuatstorageaccount.blob.core.windows.net/publicstrapiuploads/MediaLibrary/V3_Synuclein_PFF_injection_AON_Synuclein_Limbic_System_Content_Page_PD_c91b88cdce.webp)
![A stereotaxic surgery setup with a rodent, commonly used in neurological research to administer treatments with precision to specific brain regions, particularly for Parkinson's Disease (PD) studies.](https://bspuatstorageaccount.blob.core.windows.net/publicstrapiuploads/MediaLibrary/V2_Stereotaxic_Surgery_Therapeutic_Administration_Synuclein_Limbic_System_Content_Page_PD_33fbac52cc.webp)
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 chain measures in plasma & CSF (Read More in our Resource - Neurofilament Light Chain in Parkinson's Disease Models)
- Immunohistochemistry & multiplex immunofluorescence (Read More in our Presentation - Microglial activation in an α-synuclein mouse model of Parkinson's disease)
![A pair of brain tissue sections processed with immunohistochemistry (IHC) to highlight phosphorylated alpha-synuclein, which is relevant in the context of Parkinson's Disease research](https://bspuatstorageaccount.blob.core.windows.net/publicstrapiuploads/MediaLibrary/AON_p_Syn_IHC_2_Synuclein_Limbic_System_Content_Page_PD_f46c216b33.webp)
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.