An alternative secretase cleavage produces soluble Alzheimer amyloid precursor protein containing a potentially amyloidogenic sequence.
Cell culture studies have shown that the Alzheimer amyloid precursor protein (APP) is secreted after full-length APP is cleaved by a putative secretase at the Lys16-Leu17 bond (secretase cleavage I) of the amyloid peptide sequence. Because this cleavage event is incompatible with amyloid production, it has been assumed that secreted APP cannot serve as a precursor of the amyloid depositions observed in Alzheimer's disease. Here we show that in neuronally differentiated PC12 cells and human kidney 293 cell cultures a portion of the secreted extracytoplasmic APP reacted specifically with both a monoclonal antibody recognizing amyloid protein residues Leu17-Val24 and a polyclonal antiserum directed against amyloid protein residues Ala21-Lys28. Furthermore, this APP failed to react with antisera recognizing the cytoplasmic domain of the full-length protein. These data indicate the presence of an alternative APP secretase cleavage site (secretase cleavage II), C-terminal to the predominant secretase cleavage I. Depending on the exact location of cleavage site II, potentially amyloidogenic secreted APP species may be produced.
Anderson
J P
JP
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029.
Chen
Y
Y
Kim
K S
KS
Robakis
N K
NK
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000032:analysis* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000032:analysis* / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007668:Kidney / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D007930:Leucine / Q000032:analysis; D008239:Lysine / Q000032:analysis; D008969:Molecular Sequence Data; D016716:PC12 Cells; D051381:Rats; D014162:Transfection
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D007930:Leucine; D008239:Lysine