Accumulation of mA exhibits stronger correlation with MAPT than β-amyloid pathology in an APP /MAPT mouse model of Alzheimer's disease.

The study for the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular β-amyloid (Aβ) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APP MAPT mouse that at 6 months of age exhibits robust Aβ plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of Aβ pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated Aβ accumulation. The APP/MAPT mouse model also showed strong accumulation of N-methyladenosine (mA), 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 mA from mRNA, respectively. Thus, the APP/MAPT mouse recapitulates many features of AD pathology beginning at 6 months of aging.