γ-secretase substrate concentration modulates the Aβ42/Aβ40 ratio: Implications for Alzheimer disease Journal Article
| Authors: | Yin, Y. I.; Bassit, B.; Zhu, L.; Yang, X.; Wang, C.; Li, Y. M. |
| Article Title: | γ-secretase substrate concentration modulates the Aβ42/Aβ40 ratio: Implications for Alzheimer disease |
| Abstract: | Mutation of the amyloid precursor protein (APP), presenilin-1, or presenilin-2 results in the development of early onset autosomal dominant forms of Alzheimer disease (AD). These mutations lead to an increased Aβ42/Aβ40 ratio that correlates with the onset of disease. However, it remains unknown how these mutations affect γ-secretase, a protease that generates the termini of Aβ40 and Aβ042. Here we have determined the reaction mechanism of γ-secretase with wild type and three mutated APP substrates. Our findings indicate that despite the overall outcome of an increased Aβ42/Aβ40 ratio, these mutations each display rather distinct reactivity to γ-secretase. Intriguingly, we found that the ratio of Aβ42/Aβ40 is variable with substrate concentration; increased substrate concentrations result in higher ratios of Aβ42/Aβ40. Moreover, we demonstrated that reduction of γ-secretase substrate concentration by BACE1 inhibition in cells decreased the Aβ42/Aβ40 ratio. This study indicates that biological factors affecting targets such as BACE1 and APP, which ultimately cause an increased concentration of γ-secretase substrate, can augment the Aβ42/Aβ40 ratio and may play a causative role in sporadic AD. Therefore, strategies lowering the Aβ42/Aβ40 ratio through partial reduction of γ-secretase substrate production may introduce a practical therapeutic modality for treatment of AD. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | mutation; proteins; animals; mice; models, biological; carboxy terminal sequence; protein binding; in vitro study; amino acid sequence; molecular sequence data; sequence homology, amino acid; protein synthesis; peptide fragments; substrate specificity; binding sites; diseases; alzheimer disease; substrates; amyloid precursor protein; amyloid precursor protein secretases; biological factors; gamma secretase; amyloid beta-protein; protein p40; therapeutic modality; reaction kinetics; concentration (process); beta secretase; protein p42; aspartic endopeptidases |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 282 |
| Issue: | 32 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2007-08-10 |
| Start Page: | 23639 |
| End Page: | 23644 |
| Language: | English |
| DOI: | 10.1074/jbc.M704601200 |
| PUBMED: | 17556361 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 19" - "Export Date: 17 November 2011" - "CODEN: JBCHA" - "Source: Scopus" |
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