title: Mechanism of cytotoxicity mediated by the C31 fragment of the amyloid precursor protein.
abstract: The cytoplasmic tail of the amyloid precursor protein (APP) contains two putatively cytotoxic peptides, Jcasp and C31, derived by caspase cleavage of APP. Jcasp is a fragment starting from the epsilon-secretase site to position 664, while C31 is a fragment from position 665 to the C-terminus. Our studies now showed that compared to C31, Jcasp appeared to play a minor role in cytotoxicity. In particular, inhibition of Jcasp generation by treatment of gamma-secretase inhibitor did not lead to any attenuation of C31-induced toxicity. Secondly, because C31 toxicity is largely absent in cells lacking endogenous APP, we determined, using a split beta-galactosidase complementary assay to monitor protein-protein interactions, the presence of APP associated complexes. Our results demonstrated that both APP homomeric and C31/APP heteromeric complexes were correlated with cell death, indicating that C31 complexes with APP to recruit the interacting partners that initiate the signals related to cellular toxicity.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Park
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Shaked
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
authors.forename: Edward H
authors.initials: EH
authors.lastname: Koo
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001224:Aspartic Acid / Q000235:genetics; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000096:biosynthesis* / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D016564:Amyloid beta-Protein Precursor; D003603:Cytotoxins; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D010446:Peptide Fragments; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases
references.citation: Ann Neurol. 1991 Oct;30(4):572-80
references.pmid: 1789684
references.citation: J Biol Chem. 2002 Aug 9;277(32):28530-6
references.pmid: 12032152
references.citation: J Neurosci. 2006 Dec 27;26(52):13428-36
references.pmid: 17192425
references.citation: J Neurochem. 1994 Aug;63(2):495-500
references.pmid: 7913487
references.citation: Nat Med. 2000 Apr;6(4):397-404
references.pmid: 10742146
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7130-5
references.pmid: 16641106
references.citation: FASEB J. 2003 Oct;17(13):1951-3
references.pmid: 12923068
references.citation: FASEB J. 2005 Nov;19(13):1905-7
references.pmid: 16162853
references.citation: J Biol Chem. 2001 Aug 3;276(31):29045-50
references.pmid: 11397796
references.citation: Cell. 1999 Apr 30;97(3):395-406
references.pmid: 10319819
references.citation: EMBO J. 2007 Mar 21;26(6):1702-12
references.pmid: 17332749
references.citation: Nat Biotechnol. 2000 Feb;18(2):218-22
references.pmid: 10657132
references.citation: Physiol Rev. 2001 Apr;81(2):741-66
references.pmid: 11274343
references.citation: FASEB J. 2006 Jun;20(8):1254-6
references.pmid: 16636103
references.citation: J Neurochem. 2002 Jul;82(2):283-94
references.pmid: 12124429
references.citation: Mol Cell Neurosci. 2001 Nov;18(5):503-11
references.pmid: 11922141
references.citation: J Neurochem. 2003 Nov;87(3):733-41
references.pmid: 14535955