Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid β-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid β-Protein Precursor

Cerebrovascular deposition of amyloid β-protein (Aβ) is a common pathological feature of Alzheimer's disease and related disorders. In particular, the Dutch E22Q and Iowa D23N mutations in Aβ cause familial cerebrovascular amyloidosis with abundant diffuse amyloid plaque deposits. Both of these charge-altering mutations enhance the fibrillogenic and pathogenic properties of Aβin vitro. Here, we describe the generation of several transgenic mouse lines (Tg-SwDI) expressing human neuronal Aβ precursor protein (AβPP) harboring the Swedish K670N/M671L and vasculotropic Dutch/Iowa E693Q/D694N mutations under the control of the mouse Thy1.2 promoter. Tg-SwDI mice expressed transgenic human AβPP only in the brain, but at levels below those of endogenous mouse AβPP. Despite the paucity of human AβPP expression, quantitative enzyme-linked immunosorbent assay measurements revealed that Tg-SwDI mice developed early-onset and robust accumulation of Aβ in the brain with high association with isolated cerebral microvessels. Tg-SwDI mice exhibited striking perivascular/vascular Aβ deposits that markedly increased with age. The vascular Aβ accumulations were fibrillar, exhibiting strong thioflavin S staining, and occasionally presented signs of microhemorrhage. In addition, numerous largely diffuse, plaque-like structures were observed starting at 3 months of age.In vivotransport studies demonstrated that Dutch/Iowa mutant Aβ was more readily retained in the brain compared with wild-type Aβ. These results with Tg-SwDI mice demonstrate that overexpression of human AβPP is not required for early-onset and robust accumulation of both vascular and parenchymal Aβ in mouse brain.