| First Author | Jiang L | Year | 2024 |
| Journal | Front Neurosci | Volume | 18 |
| Pages | 1372297 | PubMed ID | 38572146 |
| Mgi Jnum | J:347091 | Mgi Id | MGI:7619302 |
| Doi | 10.3389/fnins.2024.1372297 | Citation | Jiang L, et al. (2024) beta-amyloid accumulation enhances microtubule associated protein tau pathology in an APP(NL-G-F)/MAPT(P301S) mouse model of Alzheimer's disease. Front Neurosci 18:1372297 |
| abstractText | 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 N(6)-methyladenosine (m(6)A), which was recently shown to be elevated in the AD brain. m(6)A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m(6)A 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. |
