Alzheimer's Disease Models & Tauopathies Models

Q: What are the key pathologic features found in the APP/PS1 transgenic mouse model?

In these transgenic mice, we find beta-amyloid (Aβ) plaque deposition beginning around 3 months-of-age, with a time-dependent increase in burden and extent. We see both fibrillar extracellular and intracellular beta-amyloid pathology, as well as parenchymal and vascular Aβ deposits. A key feature of this model is the strong level of neuroinflammation, with both astrogliosis and microgliosis (including activated microglia). You can learn more about the spatiotemporal relationships between Aβ plaques and neuroinflammatory cells in our Presentation - Amyloid-β & the Inflammatory Microenvironment in an APP/PS1 Mouse Model of Alzheimer's Disease. Multiplex immunofluorescence is a primary readout for the evaluation of therapeutic efficacy in Alzheimer's disease mouse models. Quantitative measures, such as plaque load, phosphorylated tau density, activated microglia density, reactive astrocyte density, and neuronal loss, including the spatial relationships between misfolded protein pathology (e.g. amyloid-β plaques) and neuroinflammatory cells, can be derived from digitized tissue sections using computer vision & machine learning algorithms.

Q: Are age-appropriate APP/PS1 mice readily available for studies?

Yes. We usually use 3 to 6 month-old APP/PS1 transgenic mice at the start of the dosing period. These mice are typically available to allow for rapid study initiation.

Q: What is the typical duration for studies using APP/PS1 mice?

These amyloid-β transgenic mouse models show an age-dependent progression of pathology. Depending on the mechanism-of-action & specific targets of the therapeutic intervention, as well as the specific readouts, we typically perform dosing for 3-6 months.

Q: Are activated microglia present in your Alzheimer's disease models?

Yes. Our amyloid-β and tau models show strong neuroinflammation (astrogliosis and microgliosis). These mice also show changes in microglia morphology which is consistent with that found in human Alzheimer's disease. You can read more about microglial morphology in neurodegenerative diseases in our Resource - Microglia Morphology in ALS, Alzheimer's Disease & Parkinson's Disease.

Amyloid-β Transgenic Models

The beta-amyloid pathology that is a hallmark of human Alzheimer's disease can be modelled via overexpression of mutant human amyloid precursor protein (APP) and presenilin 1 (PS1; PSEN1) in transgenic mice. Similar to human disease, the evolution of the pathology increases with age.

The APP/PS1 model that we use for preclinical evaluation of the efficacy of experimental, disease-modifying therapeutic agents is highly reproducible and replicates several key features of human AD. These mice show progressive development amyloid-beta (Aβ) plaques, cerebrovascular pathology, and neuroinflammation. The response to therapeutic intervention can be assessed by several quantitative readouts, including advanced image analysis of multiplex immunofluorescence staining of digitized brain tissue sections.

MORE INFORMATION ON AMYLOID-β MODELS

AAV Tau Mouse Models of Tauopathies

Generation of tau pathology in the adult rodent brain can be generated via injection of adeno-associated virus (AAV) vectors. In this mouse model of tauopathy (Progressive Supranuclear Palsy, Corticobasal Degeneration), wild-type (C57BL/6) mice undergo stereotaxic injection of AAV vectors overexpressing wild-type human tau into the vicinity of the substantia nigra pars compacta.

This robust tauopathy model pathologically shows phosphorylated tau aggregates in the neuron soma and neurites, neuroinflammation (including activated microglia and reactive astrocytes), neurodegeneration (including regional brain atrophy on in vivo MRI scans), and dopaminergic denervation. Significant motor deficits are observed in these tauopathy mice models resulting from the unilateral dopaminergic neuron loss, including alterations in the cylinder test, tail suspension swing test, hindlimb clasping test, and rotarod test.

More information on AAV Tau Models

Amyloid-Beta & Tau Co-Pathology Model

Our amyloid-beta (Aβ) and tau co-pathology mouse model captures two defining features of Alzheimer’s disease — Aβ plaque accumulation and tau-associated neurodegeneration — by combining transgenic and viral vector-based methodologies. This model offers a robust and translationally relevant platform for investigating disease mechanisms & assessing the efficacy of disease-modifying therapeutic interventions for Alzheimer's disease.

The amyloid-β pathology is established using APP/PS1 transgenic mice, which exhibit age-dependent Aβ plaque deposition. To induce tauopathy, adeno-associated virus (AAV) vectors encoding wild-type human tau (2N4R) are delivered via stereotaxic injection into disease-relevant brain regions. This targeted expression leads to the accumulation of phosphorylated tau aggregates within neuronal soma and processes. This co-pathology model demonstrates marked neuroinflammation, neurodegeneration, and associated functional impairments, reflecting complex pathological interactions relevant to Alzheimer's disease.

MORE INFORMATION ON AMYLOID-β & TAU CO-PATHOLOGY MODELS

ARTE10-AAV-Tau - plaque, microglia, astrocytes, and tangles

Tau Fibril Spreading Models

Generation of tau pathology in the adult mouse brain can be generated via inoculation of recombinant tau fibrils or human brain extracts. In this mouse model of Alzheimer's disease, P301S mutant tau (PS19) transgenic mice undergo stereotaxic injection of tau preformed fibrils (PFFs) into the brain to induce seeding & spreading of tau pathology.

This robust tau mouse model shows hyperphosphorylated tau aggregates in the cell bodies and processes of neurons, neuroinflammation (including activated microglia and reactive astrocytes), and neurodegeneration. Therapeutic efficacy can be evaluated using clinical assessments (e.g. change in body weight), measurement of neurofilament light chain in blood & CSF, and quantitative immunohistochemistry & multiplex immunofluorescence analysis.

More information on Tau PFF Models

A microscopic view of brain tissue, specifically highlighting tau fibrils, which are associated with neurodegenerative diseases like Alzheimer's disease

Translatability of our Alzheimer's Disease & Tauopathies Models to Human Disease

Amyloid-β Plaques & Cerebrovascular Pathology

Extracellular plaques and cerebrovascular deposits of aggregated amyloid-β are neuropathologic hallmarks of Alzheimer's disease (Serrano-Pozo, 2011). Our APP/PS1 mouse model show time-dependent increases in amyloid-β pathology (including diffuse, dense-core, and neuritic plaques, intracellular amyloid-β, and cerebrovascular pathology). The Aβ pathology progresses in a well-defined spatiotemporal pattern and can be quantified using sophisticated algorithms developed by our team.

AT8 immunofluorescence staining in the injected SNc

Tau Pathology

In addition amyloid-β, tau is a key misfolded protein found in Alzheimer's disease. Tau is thought to be the primary driver of some of the clinical and neuroimaging features of AD (Lew, 2021; Carbonell, 2025). Our APP/PS1/human Tau model demonstrates both amyloid-β and tau pathology. Phosphorylated tau staining is observed in cell bodies and processes. Tauopathies, such as Progressive Supranuclear Palsy, Corticobasal Degeneration, and Frontotemporal Dementia, show pure tau pathology in specific brain regions. In our AAV-hTau model, we are able to target tau expression to the substantia nigra and midbrain regions to effectively model tauopathies with Parkinsonian features.

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

Activated Microglia & Reactive Astrocytes

Neuroinflammatory cells, including activated microglia and reactive astrocytes, are found in close proximity to misfolded amyloid-β and tau (Minter, 2015; Chen and Yu, 2023). In our APP/PS1 mouse model, we have demonstrated a spatial and temporal relationship between Aβ plaques, activated microglia, and non-activated microglia, as well as between Aβ plaques and hypertrophic & non-hypertrophic astrocytes. We also observe a strong microgliosis and astrogliosis in relation to phosphorylated tau in our APP/PS1/hTau co-pathology and our AAV-induced tauopathy models.

Tauopathy Driven Parkinsonian Motor Features

Progressive Supranuclear Palsy and Corticobasal Degeneration are pure tauopathies which, amongst other clinical manifestations, are characterized by Parkinsonian features and severe loss of neurons in the substantia nigra (Oyangi, 2001). In our AAV-hTau model, we have found significant motor deficits (based on the Cylinder Test, Tail Suspension Swing Test, Rotarod Test, and Hindlimb Clasping Test) as a result of degeneration of dopaminergic neurons in the substantia nigra and corresponding denervation of the striatum.

Regional Brain Atrophy

Multi-modality imaging biomarkers are widely used in clinical trials of Alzheimer's disease and tauopathies. MRI-derived regional volume and cortical thickness measures are highly sensitive to brain atrophy and allow for monitoring disease progression over time in Alzheimer's disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, and Frontotemporal Dementia. Using non-invasive, in vivo whole brain MRI acquisition combined with advanced, fully-automated image processing & analysis, we have shown highly significant regional brain atrophy, specifically related to tau pathology, thereby serving as a robust in-life measure of neurodegeneration and a translational biomarker.

Alzheimer's Disease Mouse Models & Neurodegeneration

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The Interactive Presentation below allows you to explore the relationship between amyloid-β, tau, and brain atrophy in human AD and our Alzheimer's disease mouse models, including in vivo data and high-resolution images of entire Multiplex Immunofluorescence tissue sections.

You can simply navigate through this "Image Story" using the left panel.

You can pan around the high-resolution microscopy images using the left mouse button. You can zoom in and out using the mouse/trackpad (up/down) or the + and - buttons in the upper left corner. You can toggle (on/off), change color, and adjust image settings for the channels and segmentations in the Control Panel in the upper right corner.

We suggest using Full Screen Mode for the best interactive experience.

Tau, Rather than Amyloid-β, Drives Neurodegeneration in Alzheimer's Disease (AD) and Mouse Models of AD

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Alzheimer’s disease (AD) is characterized by the pathological accumulation of amyloid-β plaques and tau neurofibrillary tangles, with concurrent neurodegeneration and loss of cortical tissue. In this Interactive Presentation, we present our analysis of AD from the ADNI study and draw comparisons with findings from our amyloid-β/hTau co-pathology mouse model. We propose that a mouse model showing both tau and amyloid-β pathologies will mimic neurodegeneration and brain atrophy similar to human disease.

Our team at Biospective has performed a rigorous analysis of the relationship between amyloid-β, tau, cortical thickness, and cerebral glucose metabolism in human Alzheimer’s disease. This analysis was performed using Amyloid PET, Tau PET, FDG PET, and 3D Anatomical MRI data from the ADNI study. We have found that tau, rather than amyloid-β, is primarily responsible for cortical thinning, as well as regional cerebral glucose metabolism, which can be appreciated in the FDR-thresholded figure below.

Statistical Maps Showing the Effect of Tau and Amyloid on Cortical Thickness and Glucose Metabolism

t-Statistic maps (thresholded for statistical significance) demonstrating the effect of tau and amyloid-β on both cortical thickness and cerebral glucose metabolism.

The interactive image in the Image Viewer Panel on the right highlights strong regional associations when amyloid is high, and the video below shows how these correlations evolve as amyloid burden rises. Our findings indicate that the association between tau and cortical thickness becomes stronger with increasing amyloid-β burden.

Statistical maps showing increased regional correlation between tau and cortical thickness as a function of amyloid-β load.

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.

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

Amyloid-β and Human Tau in a Mouse Model of Alzheimer's Disease

Although many animal models have been developed to investigate Alzheimer's disease (AD), the majority are designed to replicate either amyloid-β or tau pathology in isolation. The separation of these hallmarks limits our capacity to understand the interactions of amyloid-β and tau in mediating the full clinical and pathological phenotype of AD.

To address these limitations, we have established a co-pathology model that incorporates both amyloid-β and tau pathologies within a single animal. This integrated approach provides a more holistic and translationally relevant platform for AD research.

An example of this approach is illustrated by the interactive microscopy section in the Image Viewer Panel on the right, showing a multiplex immunofluorescence (mIF) brain section from an APP/PS1/hTau mouse. The staining demonstrates amyloid-β (fibrillar), phospho-tau (AT8), and DAPI nuclear counterstaining. The high-magnification image reveals phosphorylated tau localized to neuronal soma and processes, alongside extensive fibrillar amyloid-β in plaques and vascular deposits.

https://opt003stagmediafiles.blob.core.windows.net/image/c41bec504501491d8391e55080cddd62

Illustration of Plaques and Tangles

Our co-pathology model is specifically designed to probe the potential combined effects of amyloid-β and tau on exacerbating neuronal injury, with the aim of more precisely modeling the measurable brain volume loss observed in clinical neuroimaging studies of AD patients.

In the rest of the Interactive Presentation, we will provide a detailed overview of the APP/PS1 transgenic mouse model, the process of AAV-mediated induction of co-pathology, and the MRI evidence of brain atrophy as the mouse model progresses.

Transgenic Mouse Model withe Progressive Development of Amyloid-β Pathology

ARTE10 [C57BL/6NTac.CBA-Tg(Thy1-PSEN1*M146V,-APP*Swe)10Arte] (APP/PS1) homozygous mice (Willuweit, 2009), generated on a C57BL/6NTac background, are a transgenic line incorporating the Swedish mutation of human amyloid precursor protein (APPsw) and the M146V mutation in human Presenilin 1 (PS1M146V). These mice express high levels of human amyloid-beta (Aβ) peptides via amyloidogenic processing of APP, and develop Alzheimer's disease-like amyloid pathology. This transgenic mouse model has been used for non-invasive imaging of amyloid-β plaques with Amyloid PET imaging tracers (Willuweit, 2021).

Multiplex Immunofluorescence Brain Images from ARTE10 Mice

Representative coronal brain tissue sections showing the spatiotemporal progression of amyloid-β pathology in APP/PS1 (ARTE10) mice.

Plots Showing the Progression of Amyloid-Beta Pathology in ARTE10 Mice

Quantitative analysis of the age-dependent increase in the density of amyloid-β plaques in the cerebral cortex of APP/PS1 (ARTE10) mice. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001

Our team at Biospective has also characterized the neuroinflammatory microenvironment around plaques in this model, as well as examined both microglia morphology and astrocyte morphology.

Examples of Amyloid-Beta Plaque Neighborhoods

Examples of “neighborhoods” of amyloid-β plaques to allow for microenvironment analysis.

APP/PS1 & AAV-Tau Co-Pathology Model

Our group has developed an adeno-associated virus (AAV) vector-induced mouse model of tauopathies with Parkinsonian features (e.g. Progressive Supranuclear Palsy, Corticobasal Degeneration). We have adapted this modeling strategy by injecting AAV-hTau into a transgenic APP/PS1 mouse model to generate a co-pathology model of AD.

This model was generated by injecting 6 month-old transgenic APP/PS1 (ARTE10) mice with AAV-hTau (wild-type 2N4R human tau) or AAV-null (control) vectors bilaterally into the anterior insula and the lateral entorhinal cortex using a digital stereotaxic device with an automated microinjector.

Atlas Views of Cortical Injection Sites of AAV-Tau vectors

Multiplex immunofluorescence (mIF) images were generated by immunostaining for amyloid-β (fibrillar), phospho-tau (AT8), GFAP, Iba-1, and counterstained with the DAPI nuclear stain. Tissue sections were digitized using a high-throughput slide scanner and were processed using Biospective's PERMITS^TM software platform.

Amyloid-β and Phosphorylated Tau in APP/PS1/hTau Mice (Low Magnification)

Low magnification image showing phosphorylated tau (in neuronal soma and processes) and fibrillar amyloid-β (plaques and vascular pathology. Note the extensive phosphorylated tau in the piriform cortex. For reference, an illustration with atlas labels for this approximate brain level is provided below.

Coronal Brain Atlas at the Level of the Piriform Cortex

Coronal Mouse Brain Section (Bregma -1.0) with Neuroanatomy Labels

Amyloid-β and Phosphorylated Tau in APP/PS1/hTau Mice (High Magnification)

High magnification image showing phosphorylated tau (in neuronal soma and processes) and fibrillar amyloid-β (plaques and vascular pathology). Note the extensive level of phosphorylated tau in the piriform cortex.

Brain Atrophy in the APP/PS1/hTau Model

We have acquired in vivo anatomical MRI data from wild-type (WT), WT/hTau, APP/PS1, and APP/PS1/hTau mice at 4 and 14 weeks following injection of AAV-hTau or AAV-null (control) vectors. We generated regional volumes and cortical thickness measures using our fully-automated NIGHTWING^TM image processing platform.

The interactive image in the Image Viewer Panel on the right shows a t-statistic map of the entire cortical surface comparing APP/PS1 and APP/PS1/hTau mice at 14 weeks post injection. Regions that are significantly different are highlighted in purple and blue colors. The figures below show MRI atlases and quantitative measures in several parcellated brain regions with significant differences as early as 4 weeks post injection.

Anatomical MRI with segmented regions, and plots of regional volumes assessed in wild-type (hashed), and APP/PS1 (solid), AAV-null and hTau mice. **p<0.01,***p<0.001, ****p<0.0001

Mouse brain surface rendering with segmented entorhinal cortex, as well as a plot of the regional thickness assessed in wild-type (hashed), and APP/PS1 (solid), AAV-null and hTau mice. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001

Note that APP/PS1 mice do not show any brain atrophy compared to WT mice. The injection of AAV-hTau induced highly significant reductions of regional volumes and cortical thickness. Interestingly, the APP/PS1/hTau mice appear to have greater brain atrophy compared the the WT/hTau mice, suggesting a potential modulatory role of amyloid-β.

Neuroinflammation Associated with Amyloid-β Does Not Appear to Drive Brain Atrophy

Although there is clear evidence of extensive amyloid-associated neuroinflammation, such as reactive astrocytes and activated microglia, surrounding plaques in the APP/PS1 model, these inflammatory responses do not appear to be the primary cause of neurodegeneration, as illustrated in the plot below showing the quantitative analysis of thickness in the entorhinal cortex of amyloid-β pathology.

https://opt003stagmediafiles.blob.core.windows.net/image/af7b912764fd45a4ba3c7b522b435342

Mouse brain surface rendering with segmented entorhinal cortex, as well as a plot of the regional thickness assessed in wild-type (hashed) and APP/PS1 (solid) mice. No significant difference in thickness are observed.

High magnification image showing microglia, and astrocytes. By selecting the amyloid-β channel in the top right you can appreciate the extensive level of neuroinflammation clustered around plaques.

Neuroinflammation is Also Associated with Tau Pathology

Separate from the plaque-associated neuroinflammation, there is clear evidence of tau-related neuroinflammation, including reactive astrocytes and activated microglia. More research is needed to understand how this tau-associated neuroinflammation may contribute to neurodegeneration and brain atrophy.

High magnification image showing phosphorylated tau (in neuronal soma and processes), microglia, and astrocytes. Note the extensive level of neuroinflammation in the piriform cortex.

The plots below show the quantitative analysis of Iba-1 and GFAP stain density in brain regions with amyloid-β and tau pathology.

Regional Iba1 Staining Density Analysis Praphs

Iba-1 stain density for APP/PS1/hTau compared to APP/PS1 (control) mice in Anterior, Piriform, and Entorhinal Cortex regions; mean ± SEM, t-test, *** p<0.001

Regional GFAP Staining Density Analysis Plots

GFAP stain density for APP/PS1/hTau compared to APP/PS1 (control) mice in Anterior, Piriform, and Entorhinal Cortex regions; mean ± SEM, t-test, *** p<0.001, ****p<0.0001

Summary

Alzheimer’s disease is defined by the dual pathological signatures of amyloid-β (Aβ) plaques and tau neurofibrillary tangles, alongside progressive neurodegeneration and cortical tissue loss. Traditional animal models have typically focused on these hallmarks separately, which limits our ability to explore the synergistic effects that drive disease progression in humans.

To bridge this critical translational gap, we have developed a co-pathology mouse model featuring both Aβ and tau pathology. This model is generated by introducing wild-type human tau via adeno-associated virus (AAV-hTau) into the APP/PS1 amyloid-β expressing transgenic mouse. The resulting APP/PS1/hTau mice express both pathological proteins.

By modeling both amyloid-β and tau pathologies, we demonstrate that tau is the primary driver of neurodegeneration, which is similar to what we have found in human AD. We show that significant brain atrophy and cortical thinning occur primarily when tau is present. We also show amyloid-associated neuroinflammation is not adequate to drive the neurodegeneration.

This model offers a clinically relevant platform for evaluating tau-targeted therapies and understanding disease mechanisms using biomarkers aligned with human imaging studies.

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.

Table of Contents

Learn more about our characterization of these Alzheimer's Disease & Tauopathies mouse models, our validated measures, and our Preclinical Neuroscience CRO services.

FAQs

What are the key pathologic features found in the APP/PS1 transgenic mouse model?

In these transgenic mice, we find beta-amyloid plaque deposition beginning around 3 months-of-age, with a time-dependent increase in burden and extent. We see both fibrillar extracellular and intracellular beta-amyloid pathology, as well as parenchymal and vascular Aβ deposits. A key feature of this model is the strong level of neuroinflammation, with both astrogliosis and microgliosis (including activated microglia). You can learn more about the spatiotemporal relationships between Aβ plaques and neuroinflammatory cells in our Presentation - .

is a primary readout for the evaluation of therapeutic efficacy in Alzheimer's disease mouse models. Quantitative measures, such as plaque load, phosphorylated tau density, activated microglia density, reactive astrocyte density, and neuronal loss, including the spatial relationships between misfolded protein pathology ( amyloid-β plaques) and neuroinflammatory cells, can be derived from digitized tissue sections using computer vision & machine learning algorithms.

Are age-appropriate APP/PS1 mice readily available for studies?

What is the typical duration for studies using APP/PS1 mice?

Are activated microglia present in your Alzheimer's disease models?

References

Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J.P., Petzold, G.C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., Allen, N.J., Araque, A., Barbeito, L., Barzilai, A., Bergles, D.E., Bonvento, G., Butt, A.M., Chen, W.T., … Verkhratsky, A. Reactive astrocyte nomenclature, definitions, and future directions. , : 312–325, 2021;

Keywords

a protein that plays a crucial role in maintaining the stability and function of neurons in the brain. It is predominantly found in neurons, where it stabilizes microtubules, which are part of the cell's cytoskeleton. Microtubules are essential for maintaining cell shape, enabling intracellular transport, and facilitating cellular division. Hyperphosphorylation of tau is evident in various neurodegenerative diseases, where the abnormally phosphorylated molecules lead to the detachment of tau from the microtubules. These detached tau proteins can aggregate to form insoluble fibrils, known as neurofibrillary tangles. Diseases impacted by tau aggregation are called tauopathies, and include Alzheimer's disease, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and corticobasal degeneration (CBD).

Alzheimer's Disease Mouse Models & Tauopathies Mouse Models

Amyloid-β and tau mice with age-dependent disease progression, including neurodegeneration & neuroinflammation (activated microglia & reactive astrocytes).

Amyloid-β Transgenic Models

AAV Tau Mouse Models of Tauopathies

Amyloid-Beta & Tau Co-Pathology Model

Tau Fibril Spreading Models

Translatability of our Alzheimer's Disease & Tauopathies Models to Human Disease

Alzheimer's Disease Mouse Models & Neurodegeneration

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Let us know what you’re interested in. Our team will be happy to discuss with you!