Increase in tau pathology in P290S Mapt knock-in mice crossed with App NL-G-F mice.

Abstract

Alzheimer's Disease (AD) is characterized by the pathological assembly of 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 Mapt and crossing these Mapt P290S KI mice with the App NL-G-F KI line. Mapt P290S KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in App NL-G-FxMapt P290S KI mice from 18-months of age onwards. Tau pathology was higher in limbic areas, including hippocampus, amygdala and piriform/entorhinal cortex. We also observed AT100- and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by in situ EM. Using a cell-based tau seeding assay, we showed that sarkosyl-insoluble brain extracts from both 18-month-old Mapt P290S KI and App NL-G-FxMapt P290S KI mice were seed-competent, with brain extracts from double KI mice seeding significantly more than those from the Mapt P290S KI mice. Finally, we showed that App NL-G-FxMapt P290S KI mice had neurodegeneration in the piriform cortex from 18-months of age. We suggest that App NL-G-F x Mapt P290S KI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration and aging.SIGNIFICANCE STATEMENTAlzheimer's disease (AD) is characterized by the presence of extracellular Aβ plaques and intracellular neurofibrillary tangles made of filamentous tau. The interactions between Aβ and tau pathology remain unclear. We developed a knock-in mouse model of tau pathology, expressing mutant (P290S) murine tau under its natural promoter, which exhibited a small number of tau inclusions. When these mice were crossed with a knock-in model of Aβ pathology, we observed a significant, age-dependent increase in tau pathology, along with the appearance of other key features of AD, including dystrophic neurites surrounding Aβ plaques, seed-competent tau and neurodegeneration. This suggests that this model will be useful for future studies investigating the interactions between tau and Aβ pathologies.