Pathogenic APP mutations near the γ-secretase cleavage site differentially affect Aβ secretion and APP C-terminal fragment stability

Laboratory of Neurogenetics, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium.
Human Molecular Genetics (Impact Factor: 6.39). 09/2001; 10(16):1665-71.
Source: PubMed


Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect gamma-secretase cleavage causing an increased relative ratio of Abeta42 to Abeta40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.

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    • "Among the isoforms of A␤ [39], the longer tend to be more hydrophobic and thus more prone to aggregation [2] [40], and of the two major isoforms, A␤ 42 (typically 10% of the total amyloid load, but the major form in deposited plaques) is more cytotoxic than the A␤ 40 isoform [41]. Consistent with this, several A␤PP mutations likely disturb ␥-secretase activity to increase the A␤ 42 /A␤ 40 ratio [42]. Despite these advances, the activeconformationsandchemicalpropertiesofthenormal A␤ monomers that serve as precursors in oligomer formation are currently unknown and hard to study experimentally due to their intrinsic disorder [43]. "
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    • "and may therefore not include other potential/additional benefits of lithium on Aβ toxicity. As well as the increased ratio of Aβ42 to Aβ40 peptide observed in familial AD cases with APP mutations (De Jonghe et al., 2001), increased levels of APP could also contribute to AD pathogenesis. Indeed, patients with Down syndrome have a high risk of developing AD possibly due to trisomy of the APP gene which leads to increased APP expression (Wiseman et al., 2009). "
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    • "Mutations near the cleavage site of alpha secretase (Glu693Lys, Glu693Gly, Glu693del, Asp694Asn) might change the processing of APP, in enhancing the proteolytic resistance of Abeta peptide.16,17 De Jonghe et al studied the APP mutations near the gamma secretase cleavage site.13 Missense mutations at codon 714-715 of APP decreased the secretion of Abeta 40, and the mutations at codon 716-717 increased the production and secretion of Abeta 42. "
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