Amyloid-Beta & Tau Mouse Model of Alzheimer's Disease

Biospective's Amyloid-β & Tau co-pathology mouse model of Alzheimer’s disease combines APP/PS1 transgenic mice with an AAV vector expressing human wild-type tau. This unique AD model demonstrates Aβ plaques, CAA, phosphorylated tau aggregates, neurodegeneration, and neuroinflammation. Biospective offers this validated animal model as part of its preclinical CRO services, supporting efficacy testing and target engagement studies using translational endpoints.

In this robust mouse model of Alzheimer's disease, adeno-associated virus (AAV) vectors expressing human wild-type tau are injected into the brains of APP/PS1 transgenic mice. The resulting model demonstrates amyloid-β plaques, cerebral amyloid angiopathy (CAA), intracellular phosphorylated tau aggregates, neuronal loss, and neuroinflammation (activated microglia and astrocytes), reminiscent of the pathology observed in human AD.

Biospective has extensively characterized this 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 Alzheimer’s therapeutics. As a specialized neuroscience CRO, we provide fully integrated, end-to-end services – from surgical model induction and in vivo imaging to biomarker assays and quantitative pathology – delivering high-quality, decision-ready data for biotech and pharma clients worldwide.

Overview of the Aβ & Tau Co-Pathology (APP/PS1/hTau) Model of Alzheimer's Disease

A unique animal model of Alzheimer's disease optimized for preclinical drug development.

In this model, adeno-associated virus (AAV) vectors encoding human wild-type tau undergo stereotaxic injection into disease-relevant brain regions of APP/PS1 mice. This targeted brain delivery drives high levels of toxic tau expression on the background of amyloid-beta expression, triggering a cascade of Alzheimer’s-like pathology. This rodent model faithfully recapitulates key hallmarks of AD, including:

• Aβ Plaques: Progressive development of extracellular plaques with a well-defined spatiotemporal pattern.

• Cerebral Amyloid Angiopathy (CAA): Cerebrovascular amyloid pathology in leptomeningeal vessels and penetrating arterioles. 

• Tau aggregation: Accumulation of pathogenic tau (including phosphorylated tau), forming 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 Alzheimer’s disease.

By reproducing these pathological features, the APP/PS1/hTau model provides a disease-relevant platform to evaluate therapeutic interventions under conditions that mirror the clinical hallmarks of human Alzheimer’s disease.

Amyloid-β & Tau Co-Pathology Mouse Model (APP/PS1/hTau) Generation & Study Timeline

Our expert team employs state-of-the-art, precise stereotaxic surgery techniques to induce tau pathology.

We inject high-titer AAV vectors bilaterally into AD-relevant brain regions. For 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.

For this specific model, we typically use APP/PS1 mice at ~6 months-of-age (although younger or older mice can be used).  The in vivo phase of the study typically lasts several weeks to months (depending on the starting age of the mice and the desired stage of disease). In-life readouts, such as MRI brain atrophy, show significant effects at 6 weeks following tau AAV injections. As such, generation of clinically-relevant readouts can be provided in a relatively short time frame.

Biospective has implemented a suite of  validated endpoints and Alzheimer's disease relevant biomarkers to enable clinical advancement of therapeutic programs.

To fully characterize the APP/PS1/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 co-pathology model include:

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 AD.

• Neurofilament Light Chain (NfL): A fluid biomarker of axonal damage and neurodegeneration, measured in cerebrospinal fluid (and optionally 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 AD-related pathology. We perform immunohistochemistry (IHC) and multiplex immunofluorescence for markers such as amyloid-beta, phosphorylated tau inclusions (AT8 and other antibodies), neurons (NeuN), activated microglia (Iba1), and astrocytes (GFAP). Digital image analysis of these stained tissues provides quantitative measures of Aβ plaques, 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. Neurofilament light (NfL) is a well-established marker of neurodegeneration: when neurons are damaged, NfL is released into CSF and blood, serving as a sensitive indicator of axonal injury and neurodegeneration. In clinical studies, elevated NfL levels correlate with disease progression in various neurological disorders, including Alzheimer’s disease. 

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. (See our Presentation - Amyloid-Beta & Inflammatory Microenvironment in a Mouse Model of Alzheimer's Disease). 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
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Biospective's Alzheimer's Disease Models Expertise and Services

Biospective is a global neuroscience CRO with deep expertise in Alzheimer’s disease animal models – particularly amyloid-beta and tau models, which are a core part of our service portfolio.

We have spent over 15 years developing and executing studies in Alzheimer's disease models, giving us unrivaled insight into their nuances and optimal use in drug development. Our experienced team works as an extension of your own, ensuring rigorous study design and translational relevance at every step.

Some key advantages of partnering with Biospective for Alzheimer's disease model studies include:

• Extensive Experience & Characterization: We have characterized our co-pathology mouse model through numerous studies, generating datasets that inform best practices and enhance reproducibility. This track record underscores our unique expertise with this Alzheimer's 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 bilateral AAV injections), 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/IF (e.g. Aβ, p-Tau, NeuN for neurons, Iba1 for microglia, GFAP for astrocytes) 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 mouse model 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 Alzheimer's disease models. We pride ourselves on fast project initiation, meticulous data analysis, and supporting our clients through all preclinical phases of Alzheimer’s therapy development.