AAV-Tau Mouse Models of Tauopathies

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.

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

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.

Using our PERMITS^TM 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.

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 NIGHTWING^TM 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.

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.

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.

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.

Using our PERMITS^TM 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.

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.

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.

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.

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.

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

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

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.

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

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, and increased astrocyte density and hypertrophy. 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.