TY - JOUR T1 - Increase in Tau Pathology in P290S <em>Mapt</em> Knock-In Mice Crossed with <em>App</em><sup>NL-G-F</sup> Mice JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0247-22.2022 VL - 9 IS - 6 SP - ENEURO.0247-22.2022 AU - Melissa Huang AU - Jennifer Macdonald AU - Isabelle Lavenir AU - Renren Chen AU - Molly Craxton AU - Elizabeth Slavik-Smith AU - Stephen W. Davies AU - Michel Goedert Y1 - 2022/11/01 UR - http://www.eneuro.org/content/9/6/ENEURO.0247-22.2022.abstract N2 - 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 Mapt and crossing these MaptP290S knock-in (KI) mice with the AppNL-G-F KI line. MaptP290S KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in AppNL-G-FxMaptP290S 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 in situ electron microscopy. Using a cell-based tau seeding assay, we showed that Sarkosyl-insoluble brain extracts from both 18-month-old MaptP290S KI and AppNL-G-FxMaptP290S KI mice were seed competent, with brain extracts from double-KI mice seeding significantly more than those from the MaptP290S KI mice. Finally, we showed that AppNL-G-FxMaptP290S KI mice had neurodegeneration in the piriform cortex from 18 months of age. We suggest that AppNL-G-FxMaptP290S KI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration, and aging. ER -