Tau deposition is associated with imaging patterns of calcifications and immunhistochemical markers of osteogenesis in the P301L mouse model of human tauopathy

Brain calcifications are associated with several neurodegenerative proteinopathies. Here, we report a new phenotype of imaging pattern of intracranial calcifications in transgenic P301L mice overexpressing 4 repeat human tau. P301L mice (Thy1.2) of 3, 5, 9 and 18-25 months-of-age and age-matched non-transgenic littermates (n = 4-11 per group) were assessed using in vivo / ex vivo magnetic resonance imaging with a gradient recalled echo sequence and micro computed tomography. Susceptibility weighted images computed from the gradient recalled echo data revealed regional hypointensities in the hippocampus, cortex, caudate nucleus and thalamus of P301L mice, in which corresponding phase images indicated diamagnetic lesions. In the hippocampus, occurrence of diamagnetic susceptibility calcifications increased with age. Concomitantly micro computed tomography detected hyperdense lesions. Immunochemical staining of brain sections revealed osteocalcin positive nodules, which is a marker of osteogenic maturation. Furthermore, we found vessel-associated and intra-neuronal osteocalcin positivity co-localizing with phosphorylated tau (AT8 and AT100) in the hippocampus. In contrast, osteocalcin containing nodules were vessel-associated, indicating ossified vessels, in the thalamus in absence of phosphorylated tau. In summary, we demonstrated imaging pattern of intracranial calcifications, early spheroid formation containing proteins associated with ossification along with phosphorylated tau in the P301L mouse model of human tauopathy.