Dynamic interactions of APP and Presenilin: the GxxxG dimerization motif of the A-beta sequence in amyloid production
Zusammenfassung der Projektergebnisse
Functional studies of the amyloid precursor protein APP and the homologous amyloid precursor like proteins (APLPs) and their role in signal transduction processes as well as the influence of IGF-1 on the APP-family processing were performed in cooperation with the University of Stockholm. The results from further work clearly indicate that dimerization of APP C-terminal fragments (as a substrate of the γ-secretase) via the GxxxG motif located in the transmembrane sequence (TMS) is a key factor in regulating the formation of the pathogenic Aβ42 peptides. By reduction of the dimerization strength (induced by glycine to alanine point mutations) in the wild type or familiar APP mutations (FAD-APP), we observed a constant 60% decrease in Aβ42 levels and a concomitant 3-fold increase in the amount of Aβ38. We found the FAD Presenilin 1 (PS1) mutations we analyzed as an assumption of this rule, because the decrease in Aβ42 and increase in Aβ38 level was present but much weaker than for the FAD-APP. The N-terminal contact site, formed by the flexible “loop-region“ is essential in forming the first contact of two APP molecules which were further stabilized by the TMS interactions. While the homophilic “loop” interaction of APP influences APP processing by the β-secretase, the TMS interaction modulates the γ-secretase cleavage. Both contact sites, that we characterized in great detail are promising diagnostic and therapeutic targets. Based on the results of the project, we started another successful project (Kompetenznetzwerk degenerative Demenzen, KNDD). Bericht im Tagesspiegel vom 12. April 2007 Pressemitteilung der BBAW: http://zopeman64.bbaw.de/bbaw/Presse/Pressemitteilungen/Artikel.html?id=77
Projektbezogene Publikationen (Auswahl)
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"Homo- und heterophile Oligomerisierung von APP, APLP1 und APLP2: Charakterisierung von Kontaktstellen und Cis- und Transinteraktionen". Dissertation, (1/2004-12/2007)
Daniela Kaden
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(2007). GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aß42. EMBO J, 26, 1702-12
Munter, L.M., Voigt, P., Harmeier, A., Kaden, D., Gottschalk, KE., Weise, C., Pipkorn, R., Schaefer, M. Langosch, D., and Multhaup, G.
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(2007). Homodimerization of APP: Implications for its function and metabolism. Journal of Neurochemistry, 102: 78-79
Multhaup, G, Kaden, D, Harmeier, A, Voigt, P, Schaefer, M, Munter, L
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(2007). IGF-1-induced processing of APP family proteins is mediated by different signaling pathways. J Biol Chem, 282, 10203-9
Adlerz, L., Holback, S., Multhaup, G. and Iverfeldt, K.
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“Characterization of a dimerization motif within the Aß domain of the amyloid precursor protein (APP)”. Dissertation, (5/2003-4/2007)
Lisa-Marie Münter
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(2008). Homophilic interactions of the APP ectodomain are regulated by the loop region and affect ß-secretase cleavage of APP. J Biol Chem, 283, 7271-9
Kaden, D., Munter, L., Joshi, M., Treiber, C., Weise, C., Bethge, T., Voigt, P., Schaefer, M., Reif, B. and Multhaup, G.
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(2010). Aberrant amyloid precursor protein processing in hereditary forms of Alzheimer disease mutations can be rescued by mutations in the APP GxxxG motif. J Biol Chem, 285, 21636-21634
Munter, L.M., Botev, A., Richter, L., Hildebrand, P.W., Althoff, V., Weise, C., Voigt, P., Harmeier, A., Kaden, D., and Multhaup, G.
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(2010). Isulin-like growth factor-1 (IGF-1)-induced processing of amyloid-ß precusor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases. J Biol Chem, 285, 10223-10231
Jacobsen, KT., Adlerz, L., Multhaup, G., and Iverfeldt, K.
