Abeta induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597-624).
Amyloid beta-peptide (Abeta) is postulated to play a central role in the pathogenesis of Alzheimer's disease. We recently proposed a pathway of Abeta-induced toxicity that is APP dependent and involves the facilitation of APP complex formation by Abeta. The APP-dependent component requires cleavage of APP at position 664 in the cytoplasmic domain, presumably by caspases or caspase-like proteases, with release of a potentially cytotoxic C31 peptide. In this study we show that Abeta interacted directly and specifically with membrane-bound APP to facilitate APP homo-oligomerization. Using chimeric APP molecules, this interaction was shown to take place between Abeta and its homologous sequence on APP. Consistent with this finding, we demonstrated that Abeta also facilitated the oligomerization of beta-secretase cleaved APP C-terminal fragment (C99). We found that the YENPTY domain in the APP cytoplasmic tail and contained within C31 is critical for this cell death pathway. Deletion or alanine- scanning mutagenesis through this domain significantly attenuated cell death apparently without affecting either APP dimerization or cleavage at position 664. This indicated that sequences within C31 are required after its release from APP. As the YENPTY domain has been shown to interact with a number of cytosolic adaptor molecules, it is possible that the interaction of APP, especially dimeric forms of APP, with these molecules contribute to cell death.
Shaked
G M
GM
Department of Neurosciences, University of California, San Diego, 9500 Gilman Dr., Mail Code 0691, La Jolla, California 92093-0691, USA.
Kummer
M P
MP
Lu
D C
DC
Galvan
V
V
Bredesen
D E
DE
Koo
E H
EH
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D017434:Protein Structure, Tertiary; D051381:Rats
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)