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- Title
β-amyloid accumulation enhances microtubule associated protein tau pathology in an APP<sup>NL-G-F</sup>/MAPT<sup>P301S</sup> mouse model of Alzheimer's disease.
- Authors
Lulu Jiang; Roberts, Rebecca; Wong, Melissa; Lushuang Zhang; Joy Webber, Chelsea; Libera, Jenna; Zihan Wang; Kilci, Alper; Jenkins, Matthew; Ortiz, Alejandro Rondón; Dorrian, Luke; Jingjing Sun; Guangxin Sun; Rashad, Sherif; Kornbrek, Caroline; Daley, Sarah Anne; Dedon, Peter C.; Nguyen, Brian; Weiming Xia; Takashi Saito
- Abstract
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 APPNLG-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 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 APPNL-G-F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging, and thus represents a useful new mouse model for the field.
- Subjects
TUBULINS; ALZHEIMER'S disease; TAU proteins; AMYLOID beta-protein precursor; LABORATORY mice
- Publication
Frontiers in Neuroscience, 2024, p1
- ISSN
1662-4548
- Publication type
Article
- DOI
10.3389/fnins.2024.1372297