Increase in Tau Pathology in P290S Knock-In Mice Crossed with Mice.

Alzheimer's Disease (AD) is characterized by the pathologic assembly of amyloid β (Aβ) peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aβ and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aβ pathologies by knocking the P290S mutation into murine and crossing these knock-in (KI) mice with the KI line. KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in KI mice from 18 months of age onward. Tau pathology was higher in limbic areas, including hippocampus, amygdala, and piriform/entorhinal cortex. We also observed AT100-positive and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by electron microscopy. Using a cell-based tau seeding assay, we showed that Sarkosyl-insoluble brain extracts from both 18-month-old KI and KI mice were seed competent, with brain extracts from double-KI mice seeding significantly more than those from the KI mice. Finally, we showed that KI mice had neurodegeneration in the piriform cortex from 18 months of age. We suggest that KI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration, and aging.