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Biospective's tau mouse model of PSP & CBD is a gene delivery–based preclinical model that induces rapid tau aggregation, dopaminergic neurodegeneration, neuroinflammation, and motor deficits. This unique mouse model of primary 4R tauopathy with Parkinsonian features was developed and characterized by Biospective to fill the need for a robust model of PSP & CBD that is well-suited for drug development studies.

In this robust mouse model, adeno-associated virus (AAV) vectors expressing human wild-type tau (2N4R) are delivered into the substantia nigra pars compacta via stereotaxic injection. The resulting model demonstrates tau aggregates, dopaminergic neuron loss, neuroinflammation (activated microglia and astrocytes), and motor deficits reminiscent of human 4-repeat (4R) tauopathies (PSP and CBD).

Biospective has extensively characterized this animal model and leverages it as an ideal platform for preclinical drug development, supporting high-throughput efficacy testing, mechanism-of-action studies, and target engagement evaluation for novel therapeutics for tauopathies. As a specialized neuroscience CRO, Biospective provides fully integrated, end-to-end services – from surgical model induction and in vivo imaging to translational fluid biomarker assays and quantitative pathology – delivering high-quality data for its biotech and pharma sponsors worldwide.

Overview of Our Tau Mouse Model of PSP & CBD

A rapidly inducible tau animal model of 2N4R tauopathies optimized for preclinical drug development.

In this model, adeno-associated virus (AAV) vectors encoding human wild-type 2N4R tau undergo stereotaxic injection into the midbrain substantia nigra of young adult C57BL/6 mice. This targeted intra-nigral delivery drives high levels of toxic tau expression, triggering a cascade of Parkinsonian-like pathology. Our AAV-Tau model faithfully recapitulates key hallmarks of human PSP & CBD, including:

  • Dopaminergic neuron loss: Substantial degeneration of dopamine-producing neurons in the substantia nigra pars compacta, with corresponding loss of dopaminergic nerve fibers in the striatum.

  • Tau aggregation: Accumulation of pathogenic human tau (especially phosphorylated tau), forming neurofibrillary tangle–like intracellular inclusions in affected brain regions.

  • Robust neuroinflammation: Pronounced activation of microglia and reactive astrocytes in areas of tau pathology, mirroring the neuroinflammatory response observed in human tauopathies.

  • Motor function deficits: Significant motor impairments (e.g. limb use asymmetry, coordination and balance deficits) arising from nigrostriatal neurodegeneration, reminiscent of Parkinsonian motor symptoms.

By reproducing these pathological features, our AAV-Tau model provides a disease-relevant platform to evaluate therapeutic interventions under conditions that mirror the clinical hallmarks of human 2N4R tauopathies.

Given the lack of dedicated mouse models for PSP and CBD that show Parkinsonian motor dysfunction characteristic of human disease, our proprietary model fills this gap. Our AAV-Tau model yields rapid and robust disease manifestation on an accelerated timeline. These mice develop measurable neuron loss and motor deficits within weeks of vector injection. Typically, by ~6 weeks post-injection, significant dopaminergic neuron loss in the substantia nigra is observed alongside clear behavioral deficits. This fast onset enables shorter studies and faster go/no-go decisions in preclinical programs without sacrificing biological relevance. The compressed in vivo timeline makes the AAV-Tau model highly suited for high-throughput efficacy screening and proof-of-concept studies in tauopathy research.

 

AT8 immunofluorescence staining in the injected SNc
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TH+LMX1B SN AAVTau
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AT8 immunofluorescence staining in the injected SNc 

Iba-1 and GFAP double immunofluorescence staining in the injected SNc 

Dramatic reduction of tyrosine hydroxylase staining in the ipsilateral hemisphere 

Severe loss of dopaminergic neurons in the injected SNc 

AAV-hTau Model Generation & Study Timeline

Our expert team employs state-of-the-art, precise stereotaxic surgery techniques to generate the AAV-hTau model with minimal study start-up times.

We inject high-titer AAV vectors unilaterally into the midbrain substantia nigra (SN) region of ~12-week-old C57BL/6 mice. In these surgeries, we utilize digital stereotaxic systems with automated microinjectors to ensure accurate targeting and controlled viral delivery. This refined methodology yields consistent tau expression in the substantia nigra and midbrain.

Following injection, Parkinsonian neuropathology evolves rapidly. Animals begin to exhibit motor deficits (e.g. limb use asymmetry) within a few weeks post-injection, coinciding with ongoing dopaminergic neuron loss and protein aggregation in the affected brain regions. By ~6 weeks post-AAV injection, robust disease endpoints can be captured.

An illustration of the process for AAV-hTau mouse model generation.

This abbreviated timeline is a significant advantage as it enables quicker iteration and rapid data readouts, in contrast to transgenic models that might require many months to develop endpoints. The fast onset and severity of pathology in our AAV-hTau model, therefore, provide an efficient system for testing therapeutic efficacy and mechanistic hypotheses in preclinical tau programs. Biospective can initiate studies with this model on-demand, thanks to our in-house capabilities (including ready access to viral vector stock), ensuring minimal startup time for your project.

Validated Endpoints & Translational Biomarkers

Biospective has implemented a suite of  validated endpoints and tauopathy relevant biomarkers to enable clinical advancement of therapeutic programs.

To fully characterize the AAV-hTau model and assess treatment outcomes, Biospective has validated a broad spectrum of endpoints – encompassing behavioral assays, neuroimaging, fluid biomarkers, and histopathology. This comprehensive approach yields robust, quantitative readouts for both efficacy and mechanism-of-action in preclinical studies. Key validated endpoints in our tauopathy model include:

Behavioral & Functional Endpoints

  • Hindlimb Clasping Test: A sensitive indicator of neurodegeneration (brainstem/spinal reflex integrity) often observed as disease progresses.

  • Tail Suspension Swing Test: Assesses lateral bias in movement during a tail suspension, indicating unilateral motor deficits resulting from nigrostriatal damage.

  • Cylinder Test: Measures forelimb use asymmetry during rearing and exploratory behavior. Reduced use of the contralateral paw reflects motor impairment on the side of the lesion.

Imaging, Fluid & Tissue Biomarkers

  • MRI Brain Atrophy: In vivo magnetic resonance imaging to quantify regional brain volume loss (neurodegeneration) over time. Progressive MRI-detected atrophy in the midbrain and connected structures serves as a translational endpoint paralleling human PD. MRI brain atrophy in the midbrain and striatum are observed in human PSP. MRI biomarkers are also powerful for CBD, making this endpoint highly relevant.

  • CSF Neurofilament Light Chain (NfL): A fluid biomarker of axonal damage and neurodegeneration, measured in cerebrospinal fluid (and optionally blood plasma). Elevated NfL levels indicate ongoing neuronal injury; this biomarker is also used in clinical trials, making it a valuable bridge between preclinical and clinical results.

  • Quantitative Histopathology (IHC/mIF): High-resolution tissue analyses to quantify PD-related pathology. We perform immunohistochemistry (IHC) and multiplex immunofluorescence for markers such as phosphorylated tau inclusions (e.g. AT8), dopaminergic neurons (tyrosine hydroxylase, TH), activated microglia (Iba1), and astrocytes (GFAP). Digital image analysis of these stained tissues provides quantitative measures of neurofibrillary tangle-like aggregates, neuronal loss, and neuroinflammation in the brain.

These endpoints span multiple domains – behavioral, imaging, biochemical, and histological – providing complementary measures of disease severity and therapeutic impact. Notably, the inclusion of translational biomarkers like MRI volumetry and NfL helps bridge preclinical findings to the clinic. By tracking such biomarkers longitudinally in vivo, we can quantitatively monitor disease progression and detect therapeutic effects in a way that is directly relatable to patient outcomes.

In addition to these outcome measures, Biospective distinguishes itself by offering seamless end-to-end integration of all study components. We handle every aspect of the experiment – from viral vector administration, longitudinal behavioral testing, and in vivo MRI/PET imaging to biofluid collection and post-mortem tissue analysis. Our scientific team employs advanced analytics (including automated image analysis for dopaminergic terminal density and AI-driven cell morphology classification) to extract rich datasets from the model. All data are rigorously analyzed and integrated into an interpretable report, allowing you to make informed decisions on your therapeutic candidate’s performance.

Interactive Microscopy Images
Use the Image Viewer below to navigate through high-resolution microscopy images via the left-hand panel or the on-screen arrows. You can pan around the images with your mouse, and zoom in/out using the scroll wheel or the +/- controls. The Control Panel (top-right) allows toggling of image channels and segmentation overlays. For the best experience, we recommend switching to full-screen mode.

Characterization of a Novel AAV-hTau Mouse Model of Tauopathies with Parkinsonian Features

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Tauopathies, such as Progressive Supranuclear Palsy and Corticobasal Degeneration, are rare diseases with prominent Parkinsonian features, including motor symptoms such as postural instability, vertical gaze palsy, rigidity, slowed movement (bradykinesia), muscle contractions (dystonia), and sudden jerks (myoclonus). Furthermore, individuals may face difficulties with speech and swallowing, cognitive decline, and loss of sensory perception at the cortical level. These neurodegenerative diseases are often rapidly progressing and pathologically characterized by phosphorylated tau inclusions in neurons and glia.

A significant problem for the development of disease-modifying therapeutics for tauopathies is the lack of animal models that recapitulate the human disease. To address this issue, Biospective has developed and characterized an adeno-associated virus (AAV) vector-induced mouse model that is well-suited for preclinical therapeutic efficacy studies for Progressive Supranuclear Palsy and Corticobasal Degeneration.

This Interactive Presentation illustrates some of the key motor function, neuroimaging, and pathologic features of Biospective's AAV human tau model of tauopathies with Parkinsonian features.

This model was generated by injecting 2 month-old C57BL/6 mice with AAV-hTau (wild-type 2N4R human tau) into the left substantia nigra pars compacta (SNc) and AAV-null (control) vectors into the right SNc using a digital stereotaxic device with an automated microinjector. Mice were sacrificed at 6 weeks post-injection.

Coronal Atlas with AAV Injection Site

Coronal Atlas View of SNc Injection Site

Multiplex immunofluorescence (mIF) images were generated by immunostaining for phosphorylated Tau (AT8), Conformationally Altered Tau (MC1), GFAP, Iba-1, Tyrosine Hydroxylase, Dopaminergic Nuclei, and counterstained with the DAPI nuclear stain. Tissue sections were digitized using a high-throughput slide scanner and were processed using Biospective's PERMITSTM software platform.

To navigate though this Image Story, you can use the arrows and/or the Table of Contents icon in the upper right corner of this panel.

Navigation Panel with Tooltips

You can also interact with the microscopy image in the viewer on the right at any time to further explore this high-resolution data.

Phosphorylated Human Tau Pathology

This microscopy image shows AT8 immunostaining for pTau. The ipsilateral (left hemisphere) midbrain shows extensive staining in the vicinity of the SNc and slightly beyond. For anatomical reference, an illustration with atlas labels for this brain level is provided below.

Coronal Brain Atlas at the Level of the Substantia Nigra

Coronal Mouse Brain Section (Bregma -3.2) with Neuroanatomy Labels

Tau Pathology in Neuronal Cell Bodies & Processes

This high magnification image shows extensive pTau staining in both the soma and processes of neurons in the SNc.

Conformationally Altered Tau Pathology

This low-magnification image shows MC1 immunostaining, indicating the presence of conformationally altered tau at the injection site in AAV-Tau-injected mice. Notably, the ipsilateral (left) hemisphere shows pronounced staining around the injection site.

Conformationally Altered Tau Pathology in Cell Soma & Neurites

This high-magnification image reveals extensive MC1 staining within both the cell soma and neurites of neurons located in the SNc.

Neurodegeneration in the Substantia Nigra

As can be seen in this microscopy image, there is substantial loss of TH-positive dopaminergic neurons in the ipsilateral SNc compared to the contralateral hemisphere. For reference, an illustration with atlas labels for this brain level is provided below.

Coronal Mouse Brain Section (Bregma -3.2) with Neuroanatomy Labels

Using our PERMITSTM quantitative analysis software, we have quantified the TH staining in the SNc. The plot below shows a highly significant reduction in the ipsilateral hemisphere of the AAV-Tau compared to the AAV-null (control) mice.

TH stain density for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, **** p<0.0001.

Brain Atrophy in the SNc and Midbrain

Regional brain atrophy is a key feature of tauopathies. Magnetic Resonance Imaging (MRI) is clinically used for non-invasive neuroimaging of Progressive Supranuclear Palsy (see our Resource) and Corticobasal Degeneration (see our Resource). Our team at Biospective has investigated the spatiotemporal pattern of brain atrophy in tauopathies (see MRI Measures of Disease Progression for Progressive Supranuclear Palsy Clinical Trials and MRI & Corticobasal Degeneration). We have found significant atrophy in multiple brain areas, including the midbrain and striatum in both diseases.

Given that MRI is a “translational biomarker”, we have acquired high-resolution in vivo anatomical 3D MR images from the AAV-hTau and AAV-null (control) mice using a 7T preclinical MRI scanner. We performed fully-automated image processing using our proprietary NIGHTWINGTM software and found highly significant brain atrophy in the SNc and midbrain. This data corresponds nicely to the loss of TH-positive neurons seen in the microscopy image.

MRI Brain Atlas and Volume Data for the SNc Level

Anatomical MRI with segmented SNc and midbrain, as well as plots of relative difference between ipsilateral and contralateral hemispheres for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, *** p<0.001; **** p<0.0001.

Dopaminergic Neurons in the Contralateral SNc

This microscopy image shows the contralateral (right hemisphere) SNc which demonstrates TH-positive cell bodies and processes in red. The nuclei of the dopaminergic neurons are shown in blue.

Loss of Dopaminergic Neurons in the Ipsilateral SNc

This microscopy image shows the ipsilateral (left hemisphere) SNc which demonstrates a profound reduction of TH-positive cell bodies and processes (in red) compared to the contralateral hemisphere. The dopaminergic neuron nuclei are shown in blue.

Neurodegeneration in the Caudate-Putamen & Dopaminergic Motor Deficits

This microscopy image shows severe dopaminergic denervation of the ipsilateral (left hemisphere) caudate-putamen (loss of TH-positive terminals). For reference, an illustration with atlas labels for this approximate brain level is provided below.

Atlas Section at the Striatum Level

Coronal Mouse Brain Section (Bregma +0.86) with Neuroanatomy Labels

Using our PERMITSTM quantitative analysis software, we have quantified the TH staining in the Caudate-Putamen. The plot below shows a highly significant reduction in the ipsilateral hemisphere.

Tyrosine Hydroxylase Staining in the Caudate-Putamen

TH stain density for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, **** p<0.0001.

This loss of dopaminergic innervation corresponds well with unilateral motor deficits in these mice, including a highly significant increase in use of the ipsilateral paw during the Cylinder Test, decreased latency to fall in the Rotarod Test, increased swings to the contralateral side in the Tail Suspension Swing Test (TSST), and increased Hindlimb Clasping. Additionally, early sensorimotor asymmetries were detected using the SNAP score, highlighting its utility as a sensitive measure for tracking disease progression.

Cylinder Test data for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, **** p<0.0001.

Rotarod Test data for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, **p<0.01.

Tail Swing Suspension Test (TSST) data for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, **** p<0.0001.

Hindlimb Clasping data for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, **** p<0.0001.

SNAP scores for AAV-Tau compared to AAV-null (control) injections across weeks 1, 3, and 5; mean ± SEM, t-test, **p<0.01; **** p<0.0001.

Loss of Dopaminergic Terminals in the Ipsilateral Caudate-Putamen

This high magnification view shows the severe extent of loss of dopaminergic (TH-positive) terminals in the ipsilateral striatum. There are some remaining (albeit dystrophic) axons present.

We have also identified significant brain atrophy in the caudate-putamen on MRI scans, which aligns well with our analysis of human MRI data from Progressive Supranuclear Palsy and Corticobasal Degeneration populations. This data supports the “translatability” of this tauopathy model.

MRI Atlas and Volume Data at Striatum Level

Anatomical MRI with segmented striatum, as well as plot of relative difference between ipsilateral and contralateral striatum. ****p<0.0001.

Microgliosis in Response to Human 2N4R Tau Expression

In this low magnification image, one can readily appreciate the higher density of Iba-1-positive microglia in the ipsilateral (left) hemisphere (indicated by the box) relative to the contralateral hemisphere.

The plot below shows the Iba-1 stain density in the SNc.

Plots of Iba-1 staining for AAV-Null and AAV-Tau Injected Mice

Iba-1 stain density for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, **** p<0.0001.

We have performed a morphological analysis of microglia using a novel computer vision & machine learning approach developed by our team. This fully-automated algorithm classifies non-activated (ramified) and activated (non-ramified) microglia.

Image of non-activated and activated microglia

The plot below shows the microglial activation in the SNc, with highly significant increased microglial activation in the AAV-Tau mice.

Plot of PERMITS Data Showing Activated Microglia in SNc

Microglial activation for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, **** p<0.0001.

Iba-1 Staining in Proximity to Phosphorylated Tau

This high magnification view shows the increased density of Iba-1-stained microglia in areas with phosphorylated tau aggregates.

Astrogliosis & Human Tau Pathology

This low magnification microscopy image show a higher density of GFAP-positive astrocytes in the ipsilateral hemisphere (indicated by the box). The plot below shows the GFAP stain density in the SNc.

Plot of GFAP Staining Density in SNc

GFAP stain density for AAV-Tau compared to AAV-null (control) injections; mean ± SEM, t-test, **** p<0.0001.

GFAP Staining in Proximity to p-Tau

This high magnification view shows the increased density of GFAP-stained astrocytes in areas with phosphorylated Tau aggregates.

Summary

This novel mouse model of tauopathies with Parkinsonian features recapitulates many of the hallmark features of Progressive Supranuclear Palsy and Corticobasal Degeneration, including the development of asymmetric motor dysfunction (due to unilateral injection), and associated loss of TH+ SNc neurons and striatal TH expression.

AAV-hTau regionally results in highly significant brain atrophy, elevated microglial density and activation levels, increased astrocyte density and hypertrophy, and the accumulation of pathological tau in cell soma and neurites. Further studies are planned to continue to investigate the pathologic changes in this model.

This inducible and rapidly progressing mouse model is well-suited for drug discovery with quantitative in vivo and ex vivo readouts, and possesses distinct advantages over existing transgenic models as a screening method for novel treatment options targeting tau-related pathology.

Please feel free to further explore the microscopy image in the viewer.

We would be happy to discuss this model and our characterization if you would like to Contact Us.

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This Image Interactive Presentation allows you to explore our characterization of a Novel AAV-hTau mouse model of Tauopathies with Parkinsonian features.

Biospective's Tau Mouse Model Expertise and Services

Biospective is a global neuroscience CRO with deep expertise in tau animal models – including our proprietary AAV-hTau model, which is a core part of our service portfolio.

Some key advantages of partnering with Biospective for tau model studies include:

  • Extensive Experience & Characterization: We have performed a detailed characterization of the AAV-A53T mouse model through numerous studies, generating datasets that inform best practices and enhance reproducibility. This track record underscores our unique expertise with this tauopathy model.

  • Optimized AAV Vectors & Rapid Study Start: We utilize high-titer, validated AAV vectors encoding human tau to ensure robust, consistent model induction. Biospective maintains ready access to these viral vectors in-house, enabling fast study start-up without delays. Precise stereotaxic injection techniques and optimized dosing result in reliable pathology, and our on-demand vector supply accelerates project timelines.

  • End-to-End Preclinical Services: Biospective provides fully integrated services from initial study design through execution and data analysis. Our capabilities cover all aspects of the project, including surgical model induction (skilled unilateral AAV injections into the substantia nigra), comprehensive in-life assessments (behavioral testing, motor function assays, etc.), in vivo neuroimaging (MRI, PET) for longitudinal monitoring, biofluid collection (CSF, blood) for biomarker analysis, and post-mortem histopathology (immunohistochemistry and multiplex immunofluorescence). This one-stop approach ensures consistency, quality control, and efficient timelines.

  • Translational Biomarkers & Readouts: We incorporate clinically relevant biomarkers that bridge preclinical findings to clinical outcomes. For example, we measure neurofilament light chain (NfL) levels in CSF as a biomarker of neurodegeneration (analogous to patient studies), and we perform MRI brain imaging to quantify neurodegenerative atrophy. We also conduct quantitative IHC (e.g. p-Tau, TH for dopaminergic neurons, Iba1 for microglia) and multiplex immunofluorescence to assess pathology and neuroinflammation in tissue. These advanced readouts enhance the translatability of study results to human trials.

  • Global Collaboration & Flexibility: As a global preclinical CRO, we serve biotech and pharmaceutical clients worldwide and tailor each AAV-hTau study to your therapeutic strategy. Our scientists collaborate closely with your team to customize protocols – from adjusting injection parameters (e.g. targeting specific brain regions, unilateral vs. bilateral injections) to incorporating novel endpoints or treatment paradigms. We offer flexibility to meet program-specific needs while maintaining scientific rigor, reproducibility, and transparent communication throughout the partnership.

By leveraging these strengths, Biospective empowers your team to efficiently generate decision-quality data in the AAV hTau model. We pride ourselves on fast project initiation, meticulous data analysis, and supporting our clients through all preclinical phases of tauopathy therapy development.

Contact us to discuss how our Tau mouse models and end-to-end preclinical services can support your Tau drug development program.

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Discover more of our Tauopathy Models

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FAQs

Can MRI brain atrophy be used as a translational biomarker?

Regional brain atrophy measured by MRI is a translational imaging biomarker bridging the gap between animal model studies and human clinical trials. We have published several Resources and Innovation Presentations describing the use of MRI biomarkers for Progressive Supranuclear Palsy, Corticobasal Degeneration, and Frontotemporal Dementia, including:

Is brain atrophy primarily driven by tau or amyloid-β?

Our group at Biospective has been thoroughly exploring this important topic. We have recently published a journal article in Alzheimer's & Dementia:

We have also published Innovation Presentations on this topic:

Can you quantitatively assess dopaminergic denervation of the caudate-putamen in this tauopathy model?

Yes. We use our proprietary PERMITS™ software to derive quantitative measures from digitized tissue sections. To assess dopaminergic terminal loss in the striatum, we immunostain the tissue sections for tyrosine hydroxylase (TH) and then quantify the TH-positive processes.

What is the "tail suspension swing test"?

How do you quantify "reactive" astrocytes in the AAV-Tau model?

What is an "adeno-associated virus" (AAV) vector?

Related Content

Up-to-date information on Tauopathies and best practices related to the use of translational biomarkers for the evaluation of therapeutic agents in tau animal models.

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