Amyloid-Beta & Tau Co-Pathology Mouse Model (APP/PS1/hTau)

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.

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.

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.

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.

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.

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.

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

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).

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.

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.

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.

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.

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.

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.