Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

There exist several dozen lines of transgenic mice that express human amyloid-beta protein precursor (A beta PP) with Alzheimer's disease (AD)-linked mutations. A beta PP transgenic mouse lines differ in the types and amounts of A beta that they generate and in their spatiotemporal patterns of expression of A beta assemblies, providing a toolkit to study A beta amyloidosis and the influence of A beta aggregation on brain function. More complete quantitative descriptions of the types of A beta assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how A beta toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of A beta PP transgenic mice. We measured the fraction of cortex and hippocampus occupied by densecore plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already similar to 4.5 times that of 21-month-old Tg2576 mice and similar to 15 times that of 21-24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line-and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed ADcases from the Nun Study. Cortical plaque burdens in Tg2576, APP(Swe)PS1 Delta E9, and 5XFADmice eventually far exceeded those measured in the human cohort.