In this 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 α-synuclein pathology 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
- 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.
A significant advantage of this 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 neuroinflammatory component (microgliosis and astrogliosis)
- Neurodegeneration & regional brain atrophy
- Measurable behavioral changes, such as alterations of sleep/wake cycles
- Amenable to disease modification via therapeutic intervention
A general schema for PFF model generation is:
We have the M83 transgenic mice in-licensed from the University of Pennsylvania. We maintain a well-established breeding colony in-house at Biospective, allowing us to conduct large-scale (>100 mice) studies.
For this specific model, we breed and age M83+/- male mice to 8-12 weeks-of-age. We then perform stereotaxic injection of sonicated, recombinant human α-synuclein PFFs into the AON. We use digital stereotaxic devices with automated microinjectors for high accuracy & precision.
This model is highly reproducible with a nearly 100% success rate of PFF seeding.
Our 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 (NfL) measures in plasma & CSF
- Immunohistochemistry & multiplex immunofluorescence (Read More in our Presentation - Microglial activation in an α-synuclein mouse model of Parkinson's disease)
Learn more about our characterization of this model and our validated measures.
Discover more of our Parkinson's Disease Models
Has a therapeutic effect been shown in the α-Synuclein Fibril Seeding (Limbic System) model?
Yes. That is a key advantage of this model. We have a high level of α-synuclein pathology, microgliosis, astrogliosis, and neurodegeneration, so we can demonstrate a drug effect.
A good example can be found in the paper: Nordstrõm et al., ABBV-0805, an novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease. Neurobiol. Dis., 161: 105543, 2021; doi: 10.1016/j.nbd.2021.105543.
Does Biospective observe neurodegeneration in the α-Synuclein Fibril Seeding (Limbic System) model?
Yes. We see highly elevated levels of neurofilament light (NfL) in the plasma and CSF.
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).
Are "activated" microglia present in the α-Synuclein Fibril Seeding (Limbic System) model?
Yes. In fact, we have specifically characterized that in our Presentation - Microglial activation in an α-synuclein mouse model of Parkinson's disease.
What is a "preformed fibril" (PFF)?
Recombinant, monomeric proteins (e.g. α-synuclein or tau) are incubated under specific conditions to generate aggregated, misfolded preformed fibrils. These fibrils are then sonicated to generate short fibrils that can be used for in vitro or in vivo studies.
Is the α-Synuclein Fibril Seeding (Limbic System) model readily available for studies?
Yes. We maintain a well-established breeding colony of M83 transgenic mice so that mice are readily available for studies. Mice are typically aged to 8-12 weeks prior to inoculation with α-synuclein PFFs.
How do you measure sleep in the α-Synuclein Fibril Seeding (Limbic System) model?
We use a non-invasive, high-throughput system called PiezoSleep (Learn More). We find highly reproducible, progressive alterations of the sleep/wake cycles in this model. We commonly use this test to evaluate putative disease-modifying therapeutic agents in this model.