β-amyloid accumulation enhances microtubule associated protein tau pathology in an APP^NL-G-F/MAPT^P301S mouse model of Alzheimer's 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 APP^NL-G-F knock-in mouse line was crossed to the PS19 MAPT^P301S, 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 APP^NL-G-F/PS19 MAPT^P301S 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 APP^NL-G-F/MAPT^P301S 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 microglia. The accumulation of m⁶A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively.

Discussion: Our understanding of the pathophysiology 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. The APP^NL-G-F/MAPT^P301S mouse recapitulates many features of AD pathology beginning at 6 months of aging, and thus represents a useful new mouse model for the field.