Independent generation of A beta 42 and A beta 38 peptide species by gamma-secretase

Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine-University, D-40225 Duesseldorf, Germany.
Journal of Biological Chemistry (Impact Factor: 4.6). 07/2008; 283(25):17049-54. DOI: 10.1074/jbc.M802912200
Source: PubMed

ABSTRACT Proteolytic processing of the amyloid precursor protein by beta- and gamma-secretase generates the amyloid-beta (Abeta) peptides, which are principal drug targets in Alzheimer disease therapeutics. gamma-Secretase has imprecise cleavage specificity and generates the most abundant Abeta40 and Abeta42 species together with longer and shorter peptides such as Abeta38. Several mechanisms could explain the production of multiple Abeta peptides by gamma-secretase, including sequential processing of longer into shorter Abeta peptides. A novel class of gamma-secretase modulators (GSMs) that includes some non-steroidal anti-inflammatory drugs has been shown to selectively lower Abeta42 levels without a change in Abeta40 levels. A signature of GSMs is the concomitant increase in shorter Abeta peptides, such as Abeta38, leading to the suggestion that generation of Abeta42 and Abeta38 peptide species by gamma-secretase is coordinately regulated. However, no evidence for or against such a precursor-product relationship has been provided. We have previously shown that stable overexpression of aggressive presenilin-1 (PS1) mutations associated with early-onset familial Alzheimer disease attenuated the cellular response to GSMs, resulting in greatly diminished Abeta42 reductions as compared with wild type PS1. We have now used this model system to investigate whether Abeta38 production would be similarly affected indicating coupled generation of Abeta42 and Abeta38 peptides. Surprisingly, treatment with the GSM sulindac sulfide increased Abeta38 production to similar levels in four different PS1 mutant cell lines as compared with wild type PS1 cells. This was confirmed with the structurally divergent GSMs ibuprofen and indomethacin. Mass spectrometry analysis and high resolution urea gel electrophoresis further demonstrated that sulindac sulfide did not induce detectable compensatory changes in levels of other Abeta peptide species. These data provide evidence that Abeta42 and Abeta38 species can be independently generated by gamma-secretase and argue against a precursor-product relationship between these peptides.

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    • "Interestingly, this shift in initial docking and production lines is also observed in four of the six PSEN1 mutants (Figure 5C and D). The fact that some FAD–PSEN1 mutations combine these two mechanisms (impaired fourth cycle and change in the product line preference) explains the direct and indirect correlations between Ab38 and Ab42 levels reported in the past (Czirr et al, 2008; Page et al, 2008). Our study thus demonstrates that FAD mutations cause qualitative changes in the Ab profiles by various mechanisms (Bentahir et al, 2006; De Strooper, 2007), and that decreased release of intracellular domains (Kelleher and Shen, 2010) is not an essential part of the AD pathogenic mechanism. "
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    • "sA␤PP␤ could also represent a key element between tau-and amyloidopathies. The specific fate of A␤ 38 may be related to its lower aggregation tendency when compared to A␤ 40 or A␤ 42 , as well as its distinct production pathway by the ␥ secretase [49] [50], which might be modulated by sA␤PP␤ and/or Tau. Anyway, it is quite difficult to conclude on the effect of these modifications since A␤ 38 has, to our knowledge, no specific physiological effects. "
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