Increase in Tau Pathology in P290SMaptKnock-In Mice Crossed withAppNL-G-FMice

Abstract

AbstractAlzheimer’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 murineMaptand crossing theseMaptP290Sknock-in (KI) mice with theAppNL-G-FKI line.MaptP290SKI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger inAppNL-G-FxMaptP290SKI 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 byin situelectron microscopy. Using a cell-based tau seeding assay, we showed that Sarkosyl-insoluble brain extracts from both 18-month-oldMaptP290SKI andAppNL-G-FxMaptP290SKI mice were seed competent, with brain extracts from double-KI mice seeding significantly more than those from theMaptP290SKI mice. Finally, we showed thatAppNL-G-FxMaptP290SKI mice had neurodegeneration in the piriform cortex from 18 months of age. We suggest thatAppNL-G-FxMaptP290SKI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration, and aging.