The Arctic Alzheimer mutation favors intracellular amyloid‐β production by making amyloid precursor protein less available to α‐secretase

Abstract Mutations within the amyloid‐β (Aβ) domain of the amyloid precursor protein (APP) typically generate hemorrhagic strokes and vascular amyloid angiopathy. In contrast, the Arctic mutation (APP E693G) results in Alzheimer’s disease. Little is known about the pathologic mechanisms that result from the Arctic mutation, although increased formation of Aβ protofibrils in vitro and intraneuronal Aβ aggregates in vivo suggest that early steps in the amyloidogenic pathway are facilitated. Here we show that the Arctic mutation favors proamyloidogenic APP processing by increased β‐secretase cleavage, as demonstrated by altered levels of N‐ and C‐terminal APP fragments. Although the Arctic mutation is located close to the α‐secretase site, APP harboring the Arctic mutation is not an inferior substrate to a disintegrin and metalloprotease‐10, a major α‐secretase. Instead, the localization of Arctic APP is altered, with reduced levels at the cell surface making Arctic APP less available for α‐secretase cleavage. As a result, the extent and subcellular location of Aβ formation is changed, as revealed by increased Aβ levels, especially at intracellular locations. Our findings suggest that the unique clinical symptomatology and neuropathology associated with the Arctic mutation, but not with other intra‐Aβ mutations, could relate to altered APP processing with increased steady‐state levels of Arctic Aβ, particularly at intracellular locations.