Equimolar Production of Amyloid β-Protein and Amyloid Precursor Protein Intracellular Domain from β-Carboxyl-terminal Fragment by γ-Secretase*
By N. Kakuda, S. Funamoto, Sousuke Yagishita, Mako Takami, S. Osawa, N. Dohmae, Y. Ihara. Journal of Biological Chemistry, 2006
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We showed previously that cells expressing wild-type (WT) β-amyloid precursor protein (APP) or coexpressing WTAPP and WT presenilin (PS) 1/2 produced APP intracellular domains (AICD) 49-99 and 50-99, with the latter predominating. On the other hand, the cells expressing mutant (MT) APP or coexpressing WTAPP and MTPS1/2 produced a greater proportion of AICD-(49-99) than AICD-(50-99). In addition, the expression of amyloid β-protein (Aβ) 49 in cells resulted in predominant production of Aβ40 and that of Aβ48 leads to preferential production of Aβ42. These observations suggest that ϵ-cleavage and γ-cleavage are interrelated. To determine the stoichiometry between Aβ and AICD, we have established a 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid-solubilized γ-secretase assay system that exhibits high specific activity. By using this assay system, we have shown that equal amounts of Aβ and AICD are produced from β-carboxyl-terminal fragment (C99) by γ-secretase, irrespective of WT or MTAPP and PS1/2. Although various Aβ species, including Aβ40, Aβ42, Aβ43, Aβ45, Aβ48, and Aβ49, are generated, only two species of AICD, AICD-(49-99) and AICD-(50-99), are detected. We also have found that M233T MTPS1 produced only one species of AICD, AICD-(49-99), and only one for its counterpart, Aβ48, in contrast to WT and other MTPS1s. These strongly suggest thatϵ-cleavage is the primary event, and the produced Aβ48 and Aβ49 rapidly undergo γ-cleavage, resulting in generation of various Aβ species.
Subfields: Cell Biology, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/5a63ac58b51948d3e217f9254078f2cc1334ca87
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Citations in the corpus
- Aβ Oligomers – a decade of discovery (2007, background): “The second cleavage occurs six residues C-terminal of AbVal40 and is referred to as the f-site (Zhao et al. 2004; Kakuda et al. 2006).”