β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease

作者：Lulu Jiang, Rebecca Roberts, Melissa Wong, Lushuang Zhang, Chelsea Joy Webber, Jenna Libera, Zihan Wang, Alper Kilci, Matthew Jenkins, Alejandro Rondón Ortiz, Luke Dorrian, Jingjing Sun, Guangxin Sun, Sherif Rashad, Caroline Kornbrek, Sarah Daley, Peter C. Dedon, Brian Nguyen, Weiming Xia, Takashi Saito, Takaomi C. Saido, Benjamin Wolozin · 发表于：Frontiers in Neuroscience · 年份：2024 · DOI：10.3389/fnins.2024.1372297 · 被引用次数：17 · 研究领域：RNA modifications and cancer、RNA Research and Splicing、Endoplasmic Reticulum Stress and Disease

Introduction The study of the pathophysiology study of Alzheimer’s disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. Methods The humanized APPNL-G-F knock-in mouse line was crossed to the PS19 MAPTP301S, over-expression mouse line to create the dual APPNL-G-F/PS19 MAPTP301S line. The resulting pathologies were characterized by immunochemical methods and PCR. Results We now report on a double transgenic APPNL-G-F/PS19 MAPTP301S mouse that at 6 months of age exhibits robust A plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of A pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. MAPT pathology neither changed levels of amyloid precursor protein nor potentiated A accumulation. Interestingly, study of immunofluorescence in cleared brains indicates that microglial inflammation was generally stronger in the hippocampus, dentate gyrus and entorhinal cortex, which are regions with predominant MAPT pathology. The APPNL-G-F/MAPTP301S mouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. m6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microg...