title: Frameshifted beta-amyloid precursor protein (APP+1) is a secretory protein, and the level of APP+1 in cerebrospinal fluid is linked to Alzheimer pathology.
abstract: Molecular misreading of the beta-amyloid precursor protein (APP) gene generates mRNA with dinucleotide deletions in GAGAG motifs. The resulting truncated and partly frameshifted APP protein (APP+1) accumulates in the dystrophic neurites and the neurofibrillary tangles in the cortex and hippocampus of Alzheimer patients. In contrast, we show here that neuronal cells transfected with APP+1 proficiently secreted APP+1. Because various secretory APP isoforms are present in cerebrospinal fluid (CSF), this study aimed to determine whether APP+1 is also a secretory protein that can be detected in CSF. Post-mortem CSF was obtained at autopsy from 50 non-demented controls and 122 Alzheimer patients; all subjects were staged for neuropathology (Braak score). Unexpectedly, we found that the APP+1 level in the CSF of non-demented controls was much higher (1.75 ng/ml) than in the CSF of Alzheimer patients (0.51 ng/ml) (p < 0.001), and the level of APP+1 in CSF was inversely correlated with the severity of the neuropathology. Moreover the earliest neuropathological changes are already reflected in a significant decrease of the APP+1 level in CSF. These data show that APP+1 is normally secreted by neurons, preventing intra-neuronal accumulation of APP+1 in brains of non-demented controls without neurofibrillary pathology.
authors.affiliation: Graduate School for Neurosciences, Netherlands Institute for Brain Research, 1105 AZ, Amsterdam, The Netherlands. e.hol@nih.knaw.nl
authors.forename: Elly M
authors.initials: EM
authors.lastname: Hol
authors.forename: Renske
authors.initials: R
authors.lastname: van Dijk
authors.forename: Lisya
authors.initials: L
authors.lastname: Gerez
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Sluijs
authors.forename: Barbara
authors.initials: B
authors.lastname: Hobo
authors.forename: Martijn T
authors.initials: MT
authors.lastname: Tonk
authors.forename: Annett
authors.initials: A
authors.lastname: de Haan
authors.forename: Wouter
authors.initials: W
authors.lastname: Kamphorst
authors.forename: David F
authors.initials: DF
authors.lastname: Fischer
authors.forename: Rob
authors.initials: R
authors.lastname: Benne
authors.forename: Fred W
authors.initials: FW
authors.lastname: van Leeuwen
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D011863:Radioimmunoassay; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor