BACKGROUND: Aggregation of beta-amyloid (Abeta) into oligomers and plaques is the central pathogenic mechanism in Alzheimer's disease (AD). Abeta is produced from the amyloid precursor protein (APP) by beta- and gamma-secretases, whereas, in the nonamyloidogenic pathway, alpha-secretase cleaves within the Abeta sequence, and thus precludes Abeta formation. A lot of research has focused on Abeta production and the neurotoxic 42-amino-acid form of Abeta (Abeta1-42), while less is known about the nonamyloidogenic pathway and how Abeta is degraded. OBJECTIVE: To study the Abeta metabolism in man by searching for novel Abeta peptides in cerebrospinal fluid (CSF). METHODS: Immunoprecipitation, using an anti-Abeta antibody, 6E10, was combined with either matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or nanoflow liquid chromatography and tandem mass spectrometry. RESULTS: We identified 12 truncated APP/Abeta peptides in the CSF, all of which end at amino acid 15 in the Abeta sequence, i.e. 1 amino acid before the proposed alpha-secretase site. Of these 12 APP/Abeta peptides, 11 are novel peptides and start N-terminally of the beta-secretase site. The most abundant APP/Abeta peptide starts 25 amino acids before the beta-secretase site, APP/Abeta (-25 to 15), and had a concentration of approximately 80 pg/ml. The identity of all the APP/Abeta peptides was verified in a cohort of AD patients and controls. A first pilot study also showed that the intensity of several APP/Abeta peaks in CSF was higher in AD cases than in controls. CONCLUSION: These data suggest an enzymatic activity that cleaves the precursor protein in a specific manner that may reflect a novel metabolic pathway for APP and Abeta.
BACKGROUND: Aggregation of beta-amyloid (Abeta) into oligomers and plaques is the central pathogenic mechanism in Alzheimer's disease (AD). Abeta is produced from the amyloid precursor protein (APP) by beta- and gamma-secretases, whereas, in the nonamyloidogenic pathway, alpha-secretase cleaves within the Abeta sequence, and thus precludes Abeta formation. A lot of research has focused on Abeta production and the neurotoxic42-amino-acid form of Abeta (Abeta1-42), while less is known about the nonamyloidogenic pathway and how Abeta is degraded. OBJECTIVE: To study the Abeta metabolism in man by searching for novel Abeta peptides in cerebrospinal fluid (CSF). METHODS: Immunoprecipitation, using an anti-Abeta antibody, 6E10, was combined with either matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or nanoflow liquid chromatography and tandem mass spectrometry. RESULTS: We identified 12 truncated APP/Abeta peptides in the CSF, all of which end at amino acid 15 in the Abeta sequence, i.e. 1 amino acid before the proposed alpha-secretase site. Of these 12 APP/Abeta peptides, 11 are novel peptides and start N-terminally of the beta-secretase site. The most abundant APP/Abeta peptide starts 25 amino acids before the beta-secretase site, APP/Abeta (-25 to 15), and had a concentration of approximately 80 pg/ml. The identity of all the APP/Abeta peptides was verified in a cohort of ADpatients and controls. A first pilot study also showed that the intensity of several APP/Abeta peaks in CSF was higher in AD cases than in controls. CONCLUSION: These data suggest an enzymatic activity that cleaves the precursor protein in a specific manner that may reflect a novel metabolic pathway for APP and Abeta.
Authors: Adnan Halim; Gunnar Brinkmalm; Ulla Rüetschi; Ann Westman-Brinkmalm; Erik Portelius; Henrik Zetterberg; Kaj Blennow; Göran Larson; Jonas Nilsson Journal: Proc Natl Acad Sci U S A Date: 2011-06-28 Impact factor: 11.205
Authors: Stanislav I Pekov; Daniil G Ivanov; Anna E Bugrova; Maria I Indeykina; Natalia V Zakharova; Igor A Popov; Alexey S Kononikhin; Sergey A Kozin; Alexander A Makarov; Evgeny N Nikolaev Journal: J Am Soc Mass Spectrom Date: 2019-05-09 Impact factor: 3.109
Authors: Robert Silvers; Michael T Colvin; Kendra K Frederick; Angela C Jacavone; Susan Lindquist; Sara Linse; Robert G Griffin Journal: Biochemistry Date: 2017-08-30 Impact factor: 3.162
Authors: Erik Portelius; Bin Zhang; Mikael K Gustavsson; Gunnar Brinkmalm; Ann Westman-Brinkmalm; Henrik Zetterberg; Virginia M-Y Lee; John Q Trojanowski; Kaj Blennow Journal: Neurodegener Dis Date: 2009-12-03 Impact factor: 2.977
Authors: Philipp Spitzer; Hans Wolfgang Klafki; Kaj Blennow; Luc Buée; Hermann Esselmann; Sanna-Kaisa Herruka; Connie Jimenez; Peter Klivenyi; Piotr Lewczuk; Juan Manuel Maler; Katrin Markus; Helmut E Meyer; Chris Morris; Thorsten Müller; Markus Otto; Lucilla Parnetti; Hilkka Soininen; Susanna Schraen; Charlotte Teunissen; Laszlo Vecsei; Henrik Zetterberg; Jens Wiltfang Journal: Int J Alzheimers Dis Date: 2010-09-19