title: Aβ1-15/16 as a potential diagnostic marker in neurodegenerative diseases.
abstract: Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) reflect brain biochemistry. Using combined immunoprecipitation and mass spectrometry, we have shown that amyloid beta 1-15 (Aβ1-15) is produced by concerted β- and α-secretase cleavage of amyloid precursor protein (APP) and that the relative levels of Aβ1-16 in AD compared to controls are increased. Furthermore, drug-induced γ-secretase inhibition enhances the relative levels of Aβ1-15 and Aβ1-16. Here, we investigate a novel immunoassay for Aβ1-15/16 in a broad range of neurodegenerative conditions. The CSF level of Aβ1-15/16 was measured by the bead-based amplified luminescent proximity homogeneous assay (Alpha technology). Concentrations of Aβ1-15/16 were analyzed in subjects with Parkinson disease (PD; n = 90), PD with dementia (PDD) (n = 32), dementia with Lewy bodies (DLB) (n = 68), AD (n = 48), progressive supranuclear palsy (PSP) (n = 45), multiple system atrophy (MSA) (n = 46), and corticobasal degeneration (CBD) (n = 12). The detecting antibody is specific to the C-terminal epitope of Aβ15. We found that a carboxypeptidase (CPB) present in fetal bovine serum (FBS), a component of the buffers used, degrades Aβ1-16 to Aβ1-15, which is then detected by the Aβ1-15/16 assay. Significantly, lower levels of Aβ1-15/16 were detected in PD, PDD, PSP, and MSA compared to other neurodegenerative diseases and controls. Using the specific Aβ1-15/16 assay, a reliable quantification of Aβ1-15 or Aβ1-15/16 in CSF samples is obtained. We found reduced levels of Aβ1-15 in parkinsonian disease groups. The molecular mechanism behind this reduction is at present unknown.
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital/Mölndal, S-431 80, Mölndal, Sweden. magdalena.nutu@neuro.gu.se
authors.forename: Magdalena
authors.initials: M
authors.lastname: Nutu
authors.forename: Philippe
authors.initials: P
authors.lastname: Bourgeois
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.forename: Stéphane
authors.initials: S
authors.lastname: Parent
authors.forename: Francesco
authors.initials: F
authors.lastname: Lipari
authors.forename: Sara
authors.initials: S
authors.lastname: Hall
authors.forename: Radu
authors.initials: R
authors.lastname: Constantinescu
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000818:Animals; D000918:Antibody Specificity; D015415:Biomarkers; D019921:Biotinylation; D002268:Carboxypeptidases / Q000378:metabolism; D002417:Cattle / Q000097:blood / Q000196:embryology; D003937:Diagnosis, Differential; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000276:immunology; D005260:Female; D005312:Fetal Blood / Q000201:enzymology; D006801:Humans; D007118:Immunoassay; D008163:Luminescent Measurements; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D011933:Reagent Kits, Diagnostic
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D000939:Epitopes; D010446:Peptide Fragments; D011933:Reagent Kits, Diagnostic; C480626:amyloid beta-protein (1-15); C433241:amyloid beta-protein (1-16); D002268:Carboxypeptidases