알츠하이머병 마우스 모델 및 타우병증 마우스 모델

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.