Article

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: 6.68). 09/2001; 10(16):1665-71.
Source: PubMed

ABSTRACT 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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    • "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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    • "*p < 0.05; **p < 0.01; ***p < 0.001. (range 18-100-fold), whereas the I716T and I716V (De Jonghe et al. 2001; Eckman et al. 2001) mutations produce a milder effect (2.7 and 1.3-2-fold, respectively). Next, we compared the levels of Ab40 and Ab38 as the end product of each line (Fig. 3c). "
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    • "Mutations in the amyloid precursor protein (APP) gene cause early onset autosomal-dominant Alzheimer's disease (AD) (Brouwers et al, 2008; De Strooper & Annaert, 2010; Selkoe, 2001; Wilquet & De Strooper, 2004). Pathogenic mutations (http://www.molgen.ua.ac.be/ADMutations/) located close to major APP cleavage sites (b-and g/e-sites) can increase total Ab production, but most affect the ratio of different Ab peptides without increasing total Ab, favouring a relative increase in Ab 42 versus other species (Bentahir et al, 2006; Citron et al, 1992; De Jonghe et al, 2001; Di Fede et al, 2009; Kwok et al, 2000; Scheuner et al, 1996; Suzuki et al, 1994). Ab 42 and Ab 40 are the main components of the senile plaques in AD brain "
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