The Tau[P301S] mouse remains one of the most established in vivo models for evaluating therapeutics targeting tauopathies including Alzheimer’s disease and frontotemporal dementia (FTD). Presented at AD/PD 2025 in Vienna, this poster provides comprehensive characterization across histopathological, electrophysiological, and behavioral endpoints — culminating in confirmation of compound susceptibility using a reference compound. 

Tau hyperphosphorylation was detectable from 3 to 4 months in the frontal cortex and spinal cord, with progressive rotarod decline and hippocampal long-term potentiation (LTP) deficits. Reference compound treatment ameliorated the LTP deficit, confirming pharmacological responsiveness. Plasma NfL provided a reliable in vivo biomarker throughout, and the consistent phenotype supports this model for preclinical proof-of-concept studies targeting tau pathology. 

Tauopathies, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), are driven by the accumulation of hyperphosphorylated tau, leading to progressive neurodegeneration. We aimed to comprehensively characterize the Tau[P301S] mouse model to evaluate its potential in reflecting tau-driven pathology and suitability for preclinical therapeutic testing of novel AD and FTD therapies.

Tau hyperphosphorylation, neuronal dysfunction, and motor impairments were assessed longitudinally. Plasma neurofilament light chain (NfL) was monitored as an in vivo biomarker. Tau pathology was examined histologically in the frontal cortex, spinal cord, hippocampus, and brainstem using AT8 and AT100 immunohistochemistry. Behavioral phenotyping included hippocampal LTP assessment in the CA1 region and motor testing using rotarod and clasping assays.

Tau[P301S] mice showed progressive AT8-positive tau accumulation from 3 to 4 months. At 5.5 months, significant neuronal loss (NeuN) was detected in the ventral horn of the lumbar spinal cord alongside microgliosis (CD45) and extensive AT100-positive tau accumulation. Rotarod performance declined progressively from 4 months, with near-complete failure by 5 months. LTP in hippocampal CA1 was significantly impaired at 3.5 months and was ameliorated by once-daily reference compound treatment from 1.5 to 3.5 months of age, confirming pharmacological responsiveness.

The Tau[P301S] model exhibits a strong correlation between tau hyperphosphorylation, motor impairment, and neuroinflammation — a robust, compound-susceptible platform for evaluating disease-modifying therapies for tauopathies.