An Alternative Secretase Cleavage Produces Soluble Alzheimer Amyloid Precursor Protein Containing a Potentially Amyloidogenic Sequence

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Abstract
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.