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 β (Aβ) peptide and the non-amyloidogenic in which APP is cut in the middle of the Aβ domain thus precluding Aβ formation. Using immunoprecipitation and mass spectrometry we have shown that Aβ is present in cerebrospinal fluid (CSF) as several shorter isoforms in addition to Aβ1-40 and Aβ1-42. To address the question by which processing pathways these shorter isoforms arise, we have developed a cell model that accurately reflects the Aβ isoform pattern in CSF. Using this model, we determined changes in the Aβ isoform pattern induced by α-, β-, and γ-secretase inhibitor treatment. All isoforms longer than and including Aβ1-17 were γ-secretase dependent whereas shorter isoforms were γ-secretase independent. These shorter isoforms, including Aβ1-14 and Aβ1-15, were reduced by treatment with α- and β-secretase inhibitors, which suggests the existence of a third and previously unknown APP processing pathway involving concerted cleavages of APP by α- and β-secretase.
Portelius
Erik
E
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden. erik.portelius@neuro.gu.se
Price
Eric
E
Brinkmalm
Gunnar
G
Stiteler
Mark
M
Olsson
Maria
M
Persson
Rita
R
Westman-Brinkmalm
Ann
A
Zetterberg
Henrik
H
Simon
Adam J
AJ
Blennow
Kaj
K
D053829:Amyloid Precursor Protein Secretases / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D009447:Neuroblastoma / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D053829:Amyloid Precursor Protein Secretases