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

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 Features

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The Interactive Presentation below allows you to explore our characterization of our amyloid-β and tau co-pathology (APP/PS1/hTau) mouse model, 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.

Characterization of a New Amyloid-β & Tau Co-Pathology Mouse Model of Alzheimer's Disease

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Alzheimer’s disease (AD) is pathologically defined by the presence of amyloid-β plaques and tau neurofibrillary tangles. While a broad range of animal models of AD exist, these models typically demonstrate amyloid-β or tau pathology, but not both. As such, there is a need for a “co-pathology” model which better recapitulates human disease and demonstrates features that can be measured using “translational biomarkers”.

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 Interactive Presentation illustrates some of the interesting behavioral, neuroimaging, and pathologic features of Biospective's amyloid-β/hTau co-pathology mouse model.

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.

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 microscopy image in the viewer on the right at any time to further explore this high-resolution data.

Overview of the APP/PS1 (ARTE10) Transgenic Mouse Model

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.

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

This microscopy image shows amyloid-β (fibrillar) and phospho-tau staining in an entire coronal section (anterior part of the brain) of an APP/PS1/hTau mouse. For reference, an illustration with atlas labels for this approximate brain level is provided below. You can zoom-in to observe the staining at higher magnification.

Coronal Brain Atlas at the Level of the Anterior Olfactory Nucleus

Coronal Mouse Brain Section (Bregma +2.0) with Neuroanatomy Labels

Amyloid-β, pTau, and Neuroinflammation in APP/PS1/hTau Mice (Anterior Brain; High Magnification)

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

Amyloid-β and Phosphorylated Tau in APP/PS1/hTau Mice (Middle Brain; 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 (Middle Brain; 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.

pTau, Microgliosis, and Astrogliosis in APP/PS1/hTau Mice (Middle Brain; High Magnification)

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

Amyloid-β and Phosphorylated Tau in APP/PS1/hTau Mice (Posterior Brain; 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 left entorhinal cortex (the entorhinal cortex in the right hemisphere was not injected in this brain as a control). For reference, an illustration with atlas labels for this approximate brain level is provided below.

Coronal Mouse Brain Section at the Level of the Entorhinal Cortex

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

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

High magnification image showing phosphorylated tau (in neuronal soma and processes) and fibrillar amyloid-β (plaques and vascular pathology) in the entorhinal cortex.

Sleep Alterations in APP/PS1/hTau Mice

Sleep is altered in Alzheimer’s disease and has been associated with tau-driven neuropathology. Increased daytime sleep has been observed in later stages of the disease.

We have performed an assessment of sleep-wake cycles in the APP/PS1/hTau model using the non-invasive PiezoSleep system. The plot below shows the increased level of sleep in the dark phase in APP/PS1/hTau mice compared to APP/PS1 mice (corresponding to daytime sleep in humans).

PiezoSleep System Illustration and Plot of Sleep Percentage

Percentage of sleep in the light and dark phases measured by the PiezoSleep system.

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 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 figures below show MRI atlases and quantitative measures in several brain regions.

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.

Translation of Mouse MRI Brain Atrophy Data to Human Alzheimer's Disease

Our team at Biospective has performed a rigorous analysis of the relationship between amyloid-β, tau, and cortical thickness in human Alzheimer’s disease. This analysis was performed using Amyloid PET, Tau 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 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.

We have further demonstrated that the correlation between tau and cortical thickness is increased as the amyloid-β burden increases, which is apparent in the video below.

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

This human neuroimaging data corresponds well with our mouse MRI data showing that tau is the primary driver of brain atrophy with an apparent increase in the presence of amyloid-β.

Summary

This novel amyloid-β/tau co-pathology mouse model recapitulates several features of Alzheimer’s disease. In terms of the neuropathology, we have observed parenchymal (including diffuse, dense-core, and neuritic plaques) and vascular Aβ aggregates, phosphorylated tau in cell bodies and processes (including dystrophic neurites), microgliosis, and astrogliosis. We plan to further explore the relationships between the misfolded proteins and neuroinflammation in this model.

One of the most interesting observations is the neurodegenerative phenotype in the APP/PS1/hTau mice. The regional brain atrophy observed via structural analysis of the anatomical MRI scans can provide a robust way to evaluate the effects of potential interventions and serve as a translational biomarker given the widespread use of neuroimaging in AD clinical trials.

Based on the quantifiable in-life and post-mortem measures that we have reported, APP/PS1/hTau mice can serve as a useful model for preclinical evaluation of novel disease-modifying therapeutics for Alzheimer’s disease.

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

Section: Coronal Section 1

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Channels

Nuclei (DAPI)

Astrocytes (GFAP)

Microglia (Iba-1)

Amyloid-β

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

Tau Fibril Spreading Models

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

Alzheimer's Disease Mouse Models Features

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