Transgenic Tau Mouse Models – Transgenic PS19 Mouse Model

In the PS19 mouse model, tau pathology develops in a progressive and age-dependent manner. Indeed, InnoSer’s internal data have demonstrated that hyperphosphorylated tau species (AT8+) are typically detectable from approximately 5–6 months of age, with more robust and reproducible neurofibrillary tangle–like pathology observed at approximately 8–9 months of age, detected in total hippocampus as well as individual hippocamal subregions and across the somatomotor cortex. 

The model expresses human MAPT carrying the P301S mutation under the murine prion protein (PrP) promoter, which drives high neuronal expression and ultimately leads to widespread tau aggregation and neurodegeneration. However, variability in pathology burden at intermediate ages has been reported, which should be considered when powering studies or selecting treatment start ages. Indeed, an extensive study comparing PS19 and Tau[P301S] phenotypes has highlighted variability in pathology at even 8 months of age in the PS19 line, reporting that some mice had 3-fold more tau prions compared to others (Woerman et al., 2017). 

For programs requiring earlier and more tightly controlled onset of tau pathology, in turn enabling shorter preclinical efficacy timelines, InnoSer’s Tau[P301S] mouse model may offer strategic advantages due to its accelerated and reproducible phenotype. 

Read more about the Tau[P301S] mouse model, its applicability for your therapeutic program as well as study timelines, readouts and example data here.

No, the PS19 model is a pure tauopathy model and does not develop amyloid-β plaques. Similar to other single transgenic mouse models featuring human disease-associated mutations in the MAPT gene, these models do not carry APP or PSEN mutations, lacking amyloid-driven pathology. This makes the PS19 line particularly suitable for preclinical efficacy studies aiming to evaluate programs of tau-targeted therapeutics in isolation, including anti-tau antibodies, aggregation inhibitors, microtubule stabilizers, and tau-directed gene therapies.  

However, Alzheimer’s disease is biologically defined by the interaction between amyloid and tau pathology. If you are developing programs targeting upstream amyloid mechanisms — such as BACE1 inhibition, γ-secretase modulation, or anti-Aβ antibodies, your preclinical pipeline may benefit from amyloid-driven models such as the APP[V717I] mouse model and/or the APP[V717I]xPS1[A246E] mouse model. For combined amyloid–tau interaction studies, model selection should align with the therapeutic mechanism of action and intended clinical positioning.

Yes, cognitive and behavioural deficits have been reported in the PS19 mouse model, although findings depend on age, as well as the background strain. PS19 mice on mixed background were shown to have impairments in learning and memory in Morris Water Maze test at 6 months of age (Takeuchi et al., 2011) and 7.5 months of age (Lasagna-Reevers et al., 2016). However, motor impairments (Sun et al., 2020) that emerge with disease progression in this mouse model may interfere with swimming performance, potentially confounding cognitive readouts in this task. This is an important consideration when selecting behavioral endpoints for tauopathy studies in PS19 mice. 

At InnoSer, we therefore place strong emphasis on spontaneous and home-cage–like behavioral assessments using automated systems such as the PhenoTyper. We’ve demonstrated that across longitudinal studies, PS19 mice displayed alterations in spontaneous behavior at later stages (e.g., ~33 weeks of age), including increased overall activity and shorter arrest durations compared to non-transgenic controls.  

Overall, although PS19 mice exhibit measurable behavioral alterations, particularly in spontaneous activity paradigms, cognitive readouts can be influenced by motor phenotypes and inter-animal variability.  

Careful selection of behavioral endpoints is therefore critical when designing preclinical efficacy studies in this model.

Our experts are happy to advise on the most appropriate behavioral strategy for your Tau-targeting program – reach out to us now.

Yes, internal validation experiments carried out at InnoSer have demonstrated that the PS19 mouse model develops progressive neuroinflammation as well neurodegeneration, including neuronal loss and brain atrophy at later disease stages observed from 8 months of age. In this mouse model, tau pathology (AT8+ areas) is associated with mild neuroinflammatory phenotype marked by astrogliosis (GFAP+) and microgliosis (Iba+, MHC-II+ and CD11b+) beginning at 5.5 months of age, which becomes more pronounced from 8 months of age.  

In line, InnoSer’s internal validation experiments, we have confirmed that the neurodegeneration phenotype in the PS19 mice is marked by significant increase of ventricle volume, accompanied by loss of neuronal cells (detected via IHC using markers such as NeuN) across the CA1 and CA3 regions of the hippocampus, with a larger extent in the CA3 region.  This phenotype enhances its translational relevance for evaluating disease-modifying therapies aimed at preventing neurodegeneration rather than solely reducing tau aggregates. 

Reach out to InnoSer’s study team to obtain full PS19 mouse model validation data.

The PS19 mouse model is a suitable background transgenic mouse model of tau pathology that can be used to study the seeding and spreading of tau using recombinant and/or patient-derived tau seeds and/or brain extracts, respectively. The presence of mutant human P301S tau makes the model highly responsive to intracerebral injection of pathological tau seeds, accelerating aggregation and enabling mechanistic studies of tau transmission. 

In traditionally used transgenic models such as the PS19, pathology arises cell-autonomously in many neurons at the same time, in turn making it difficult to distinguish between intracellular development of tau pathology from true prion-like spreading of tau pathology across connected brain regions.   

In mouse models of tau seeding and spreading, tau aggregates are injected into the hippocampus of transgenic tau mouse models. Tau aggregates are injected into transgenic tau mice at young ages whereby the mice show minimal or no tau aggregation pathology. In this way, endogenous (non-aggregated) tau in transgenic mice is used as a background, allowing controlled recruitment of tau aggregation and pathological propagation of the injected tau aggregates.   

However, baseline variability in endogenous tau pathology levels at certain ages may influence experimental outcomes and should be accounted for in study design. 

For programs requiring highly standardized baseline pathology prior to seeding or therapeutic intervention, InnoSer’s Tau[P301S] mouse model may provide improved reproducibility and controlled study initiation windows. 

Learn more about InnoSer’s expertise in performing efficacy studies in tau seeding and spreading mouse models here.