Pathogenic Mechanisms of the Arctic Alzheimer Mutation

Sammanfattning: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by neurofibrillay tangles and deposition of amyloid-? (A?) peptides. Several mutations in the gene for amyloid precursor protein (APP) cause familial AD and affect APP processing leading to increased levels of A?42. However, the Arctic Alzheimer mutation (APP E693G) reduces A? levels. Instead, the increased tendency of Arctic A? peptides to form A? protofibrils is thought to contribute to the pathogenesis.In this thesis, the pathogenic mechanisms of the Arctic mutation were further investigated, specifically addressing if and how the mutation affects APP processing. Evidence of a shift towards ?-secretase cleavage of Arctic APP was demonstrated. Arctic APP did not appear to be an inferior substrate for ?-secretase, but the availability of Arctic APP for ?-secretase cleavage was reduced, with diminished levels of cell surface APP in Arctic cells. Interestingly, administration of the fatty acid docosahexaenoic acid (DHA) stimulated ?-secretase cleavage and partly reversed the effects of the Arctic mutation on APP processing.In contrast to previous findings, the Arctic mutation generated enhanced total A? levels suggesting increased A? production. Importantly, this thesis illustrates and explains why measures of both Arctic and wild type A? levels are highly dependent upon the A? assay used, with enzyme-linked immunosorbent assay (ELISA) and Western blot generating different results. It was shown that these differences were due to inefficient detection of A? oligomers by ELISA leading to an underestimation of total A? levels.In conclusion, the Arctic APP mutation leads to AD by multiple mechanisms. It facilitates protofibril formation, but it also alters trafficking and processing of APP which leads to increased steady state levels of total A?, in particular at intracellular locations. Importantly, these studies highlight mechanisms, other than enhanced production of A? peptide monomers, which could be implicated in sporadic AD.