Tauopathy Mouse Models – Seeding and Spreading Tau mouse models

A species barrier restricts prion transmissions across species, determining the infectivity of pathogenic prions. Given that tauopathies present in a similar way to prion diseases, working with human patient-derived tau aggregates injected into mouse models could imply that pathogenic human tau aggregates would not induce pathology due to “incompatibility” between the two tau species – from human and mouse origins, respectively.  

In InnoSer’s Tau seeding and spreading models, this is not a limiting factor, as we use transgenic mice expressing human tau. Although low levels of endogenous mouse tau will be present in these transgenic tau mouse models, they will not act as the main substrate for aggregation in models of seeding and spreading.  

Similarly, at the ages (2 months of age) for tau seeding experiments, endogenous pathological tau is minimal, and the injected human tau aggregates interact primarily with soluble (non-aggregated) human tau expressed by the transgene of the mouse model, enabling efficient prion-like propagation of tau in accordance with the scientific literature (Ahmed et al., 2014; Clavaguera et al.,2009).  

This design allows robust and reproducible assessment of Tau seeding, spreading, and target engagement in a human-relevant Tau context. 

Yes, as a preclinical CRO specialized in neurodegenerative disease models and tauopathies, InnoSer frequently works with patient-derived tau material for in vivo tau seeding studies. InnoSer has access to post-mortem brain extracts obtained from patients with tau-relevant neurodegenerative diseases, including frontotemporal dementia (FTD), Alzheimer’s disease, and other primary and secondary tauopathies.  

In addition to working with patient-derived material, InnoSer also performs seeding studies using aged brain extracts from the Tau[P301S] mouse model, recombinant Tau fibrils (Stressmarq) and/or synthetic preformed fibrils (PFFs).  

While InnoSer frequently performs studies using in-house established and validated seeding mouse models, including Tau[P301S] using seeds from end-stage mice of the same line, and/or the Tau[P301L] using recombinant seeds, we have also carried out multiple studies using human brain extract samples from multiple tauopathies (including Alzheimer’s disease and frontotemporal dementia) in commonly utilized tau lines such as the PS19 and/or the hTau model (described by Andorfer et al.,2003).  

Interested in evaluating your therapeutic candidate in a strain-specific Tau seeding model? Reach out to InnoSer’s neurodegeneration team to discuss the most suitable approach for your program. 

In InnoSer’s tau seeding mouse models, tau aggregates are delivered via stereotactic injection into the hippocampus, typically targeting the CA1 region. Following injection, we observe rapid induction of Tau pathology locally (i.e., 9 weeks post-injection in the Tau[P301S] mouse model; you can refer to a subset of the validation data here), with subsequent anatomically connected spread across the hippocampal formation, including the dentate gyrus and CA fields, as well as propagation toward the entorhinal cortex and cortical regions. Further statistical analyses (correlation of pathology, AT8+ signal, in the two regions) performed by InnoSer’s team suggest that the observed distribution pattern reflects pathological spread from the ipsilateral to contralateral sides rather than diffusion of tau aggregates from the injection itself.  

InnoSer’s robust in-house characterization of induction kinetics, anatomical progression, including semi-quantitative data on tau pathology, as well as related neuroinflammation to ensure high scientific validity and reproducibility for preclinical anti-Tau therapeutic testing. 

Interested in reviewing our full validation dataset or discussing whether a Tau seeding model fits your mechanism of action? 

Reach out to InnoSer’s experts to obtain full validation slide decks.  

InnoSer’s tau[P301S] mouse model arises as a highly suitable background mouse model to study efficacy of therapeutics on pathologic tau seeding and propagation. Both heterozygous and homozygous Tau[P301S] genotypes are available for studies, with each differing in resulting pathology.  

In InnoSer’s studies, both genotypes are typically injected with aged brain extracts obtained from end-stage (5-5.5 months old) homozygous Tau[P301S] mice due to the fact that the overexpression of human mutant P301S tau is more aggregation-prone than other mutations.  

Due to higher transgene expression, homozygous mice develop faster and more aggressive Tau pathology. Typically injected at ~2 months of age, they show robust seeded pathology within 9 weeks post-injection, making them highly suitable for rapid proof-of-concept and direct anti-Tau efficacy studies. 

In contrast, heterozygous Tau[P301S] mice exhibit lower levels of Tau seeding and spreading. When injected at ~6 months of age and analyzed 9 weeks later, they develop measurable Tau pathology accompanied by astrogliosis and microgliosis, providing a more moderate and extended window to evaluate therapeutic effects on both Tau propagation and associated neuroinflammation. 

Reach out to InnoSer to discuss which Tau[P301S] mosue model seeding background best aligns with your therapeutic strategy.