Amyloid precursor protein and BACE function as oligomers.
Processing of the amyloid precursor protein (APP) by beta- and gamma-secretases leads to the generation of amyloid-beta (Abeta) peptides, which are the toxic agents in the pathogenesis of Alzheimer's disease. The molecular reasons for the sequential Abeta generation by secretase activities have remained unclear. Our studies support an oligomerization-dependent mechanism for the conversion of APP into Abeta. By different lines of evidence, we showed that APP is capable of forming homodimers and tetramers. Oligomerization of APP occurs in a zipper-like mechanism primarily mediated by two highly conserved sites of the ectodomain. We also found that in human brain tissue beta-secretase (BACE) occurred as a dimer, whereas the soluble ectodomain of truncated BACE exclusively occurred in the monomeric form. A mutational analysis of the active sites supports the idea that BACE might have acquired a specific catalytic activity by oligomerization, which is stabilized through the transmembrane and the cytoplasmic domains. Our results predict that APP homodimers are functionally active within the plasma membrane and most likely represent substrates for BACE oligomers. Understanding the molecular tasks of homophilic binding of substrates and secretases will allow to find secretase inhibitors which specifically bind to contact sites of dimers and thus inhibit Abeta formation.
Multhaup
Gerd
G
Institute of Chemistry and Biochemistry, Free University of Berlin, Berlin, Germany. multhaup@chemie.fu-berlin.de
D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D001921:Brain / Q000201:enzymology / Q000473:pathology; D006801:Humans
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human