The Arctic mutation interferes with processing of the amyloid precursor protein

The Arctic amyloid precursor protein (APP) Alzheimer mutation, is located inside the beta-amyloid (Abeta) domain. Here, hybrid APP mutants containing both the Swedish and the Arctic APP mutations were investigated. ELISA measurements of cell media showed decreased levels of both Abeta40 and Abeta42. Similar results were obtained for the Dutch and Italian mutations, whereas the Flemish mutation displayed increased amounts of Abeta40 and Abeta42. Immunoprecipitation studies revealed increased Abeta40/p3(40) and Abeta42/p3(42) ratios for the Arctic mutation. These results were further verified by quantification revealing decreased levels of alphaAPPs accompanied by increased betaAPPs levels in the media. Thus, the pathogenic effects of the Arctic mutation may not only be due to the changed properties of the peptide but also altered processing of Arctic APP.