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Identification of novel APP/Abeta isoforms in human cerebrospinal fluid.

Artikel i vetenskaplig tidskrift
Författare Erik Portelius
Gunnar Brinkmalm
Ai Jun Tran
Henrik Zetterberg
Ann Brinkmalm-Westman
Kaj Blennow
Publicerad i Neuro-degenerative diseases
Volym 6
Nummer/häfte 3
Sidor 87-94
ISSN 1660-2862
Publiceringsår 2009
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor 87-94
Språk en
Länkar dx.doi.org/10.1159/000203774
Ämnesord Aged, Aged, 80 and over, Alzheimer Disease, cerebrospinal fluid, Amino Acid Sequence, Amyloid Precursor Protein Secretases, metabolism, Amyloid beta-Protein, cerebrospinal fluid, metabolism, Amyloid beta-Protein Precursor, cerebrospinal fluid, metabolism, Chromatography, Liquid, Female, Humans, Immunoprecipitation, Male, Molecular Sequence Data, Pilot Projects, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Ämneskategorier Psykiatri

Sammanfattning

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.

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