Transgenic Tau Mouse Models – Tau[P301L] Mouse Model

Both Tau[P301S] (originally described by Allen et al., 2002) and Tau[P301L] (originally described by Terwell et al., 2005) mouse models feature pathogenic mutations in the human MAPT gene, which are associated with various forms of familial frontotemporal lobar degeneration (FTLD). However, they differ markedly in the development of tau disease pathophysiology and thus, experimental utility.  

In the Tau[P301L] model, tau pathology develops more gradually, with more variable and later onset of neurofibrillary tangle–like pathology occurring around 7-8 months of age. In this model, tau pathology is limited to the brain stem (and spinal cord) with a decreasing extent in the midbrain and cerebral cortex. Although Tau[P301L] mice show progressive, age-dependent deficits in motor function (beam walk, clasping phenotype), these are present starting from 7 months of age, with robust, detectable deficits occurring at 9 months of age.  This slower disease progression makes the Tau[P301L] model more suitable for longitudinal studies focused on disease evolution, chronic treatment paradigms, and mechanisms underlying progressive tau aggregation.  

In contrast, InnoSer’s in-depth characterization of the Tau[P301S] model demonstrates early and robust tau-associated pathology, including pronounced tau hyperphosphorylation and accumulation of insoluble Tau species starting as early as 4.5 months of age and progressing rapidly until 6 months, when widespread and severe pathology is present. Tau pathology extends across cortex, hippocampus, and brainstem, and is accompanied by neuroinflammation and neuronal loss in the spinal cord (van Olst et al., 2020) and superficial layers of the cortex, also measured by the increased Neurofilament Light in plasma and CSF. Robust motor deficits confirmed by InnoSer’s team at 4.5 months of age, and cognitive deficits in Morris water maze performance and age-dependent hippocampal LTP impairment emerging from ~3.5 months of age. This rapid and consistent phenotype enables you to perform reproducible preclinical efficacy and target-engagement studies with short in vivo study timelines.  

Taken together, InnoSer generally recommends running efficacy studies in the Tau[P301S] model due to its rapid, consistent and predictable tau pathology and behavioral phenotype, helping you obtain quick preclinical decisions. 

The Tau[P301L] model may be better suited for studies requiring extended observation of tauopathy progression. 

Reach out to InnoSer’s expert team to discuss which Tau mouse model is the most suitable for your research.