Transgenic mice with the Arctic APP mutation show an age-dependent increase in Aβ levels

The pathological mechanisms by which the Arctic APP mutation (E693G) within the amyloid-beta (Aβ) peptide cause dementia has not been clarified, but in vitro studies have demonstrated that the Arctic mutation alters the properties of the Aβ peptide, resulting in formation of protofibrils more rapidly and at higher levels compared to wild-type Aβ. We have generated a transgenic mouse model expressing human APP695 with the Arctic mutation (TgAPParc), which is the only reported in vivo model characterizing the effect of the Arctic APP mutation without the influence of other APP mutations. Heterozygous TgAPParc mice show amyloid deposition in thalamus and subiculum, starting at 7 months of age, which is associated with impaired spatial learning and memory at 15 months in female transgenic mice. Here we report a biochemical characterization of Aβ levels in transgenic mice expressing hAPParc at about a 3-fold level compared to mouse endogenous APP. Aβ40 and Aβ42 levels were measured by ELISA in diethylamine (DEA)-soluble and formic acid (FA)-soluble brain extracts from wildtype and transgenic littermates at different ages (6, 12, 18 and 24 months of age). The levels of human Aβ40 and Aβ42 were below the limit of detection in the DEA-soluble brain extracts. However, the TgAPParc mice show an age-dependent increase in both Aβ40 and Aβ42 in FA-soluble brain extracts, starting around 12 months of age. In summary, our findings show that a relatively low level of hAPParc overexpression is sufficient to cause an age-dependent increase in both Aβ40 and Aβ42 in FA-soluble brain extracts, suggesting that the majority of Aβ in the brains of the TgAPParc mice is highly aggregated. This is in line with the previous in vitro reports of increased protofibril formation caused by the Arctic APP mutation.