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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    ABSTRACT: The greatest risk factor for Alzheimer's disease (AD) is age, and changes in the ageing nervous system are likely contributors to AD pathology. Amyloid beta (Aβ) accumulation, which occurs as a result of the amyloidogenic processing of amyloid precursor protein (APP), is thought to initiate the pathogenesis of AD, eventually leading to neuronal cell death. Previously, we developed an adult-onset Drosophila model of AD. Mutant Aβ42 accumulation led to increased mortality and neuronal dysfunction in the adult flies. Furthermore, we showed that lithium reduced Aβ42 protein, but not mRNA, and was able to rescue Aβ42-induced toxicity. In the current study, we investigated the mechanism/s by which lithium modulates Aβ42 protein levels and Aβ42 induced toxicity in the fly model. We found that lithium caused a reduction in protein synthesis in Drosophila and hence the level of Aβ42. At both the low and high doses tested, lithium rescued the locomotory defects induced by Aβ42, but it rescued lifespan only at lower doses, suggesting that long-term, high-dose lithium treatment may have induced toxicity. Lithium also down-regulated translation in the fission yeast Schizosaccharomyces pombe associated with increased chronological lifespan. Our data highlight a role for lithium and reduced protein synthesis as potential therapeutic targets for AD pathogenesis.
    Frontiers in Aging Neuroscience 07/2014; 6:190. DOI:10.3389/fnagi.2014.00190 · 2.84 Impact Factor
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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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    ABSTRACT: Autosomal-dominant Alzheimer's disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on APP mutations to-date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD-associated APP I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO-K1 cells. All APP I716 mutations increased the ratio of Aβ42/40 and changed the product line preference of γ-secretase towards Aβ38 production. In addition, the APP I716F mutation impaired the ε-cleavage and the fourth cleavage of γ-secretase and led to abnormal APP β-CTF accumulation at the plasma membrane. Taken together, these data indicate that APP mutations at the same codon can induce diverse abnormalities in APP processing, some resembling PSEN1 mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different APP mutations at the same position. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 10/2013; DOI:10.1111/jnc.12466 · 4.24 Impact Factor
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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 ( 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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