A novel pathway for amyloid precursor protein processing

Amyloid precursor protein (APP) can be proteolytically processed along two pathways, the amyloidogenic that leads to the formation of the 40-42 amino acid long Alzheimer-associated amyloid beta (A beta) peptide and the non-amyloidogenic in which APP is cut in the middle of the A beta domain thus precluding A beta formation. Using immunoprecipitation and mass spectrometry we have shown that A beta is present in cerebrospinal fluid (CSF) as several shorter isoforms in addition to A beta 1-40 and A beta 1-42. To address the question by which processing pathways these shorter isoforms arise, we have developed a cell model that accurately reflects the A beta isoform pattern in CSF. Using this model, we determined changes in the A beta isoform pattern induced by alpha-, beta-, and gamma-secretase inhibitor treatment. All isoforms longer than and including A beta 1-17 were gamma-secretase dependent whereas shorter isoforms were gamma-secretase independent. These shorter isoforms, including A beta 1-14 and A beta 1-15, were reduced by treatment with alpha-and beta-secretase inhibitors, which suggests the existence of a third and previously unknown APP processing pathway involving concerted cleavages of APP by alpha- and beta-secretase. (C) 2009 Elsevier Inc. All rights reserved.