Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice

Accumulation of amyloid- (A) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer's disease (AD). After almost 15years from their generation, 3xTg-AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg-AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed A and tau load, neuroinflammation, and cognitive changes in 2-, 6-, 12-, and 20-month-old female 3xTg-AD and nontransgenic (NonTg) mice. We found that similar to 80% of the mice analyzed had A plaques in the caudal hippocampus at 6months of age, while 100% of them had A plaques in the hippocampus at 12months of age. Cortical A plaques were first detected at 12months of age, including in the entorhinal cortex. Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6-month-old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age. Neuroinflammation was first evident in 6-month-old mice and increased as a function of age. These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD-like pathology in female 3xTg-AD mice, and will facilitate the design of future studies using these mice.