title: Altered cerebrospinal fluid levels of amyloid β and amyloid precursor-like protein 1 peptides in Down's syndrome.
abstract: Down's syndrome (DS) patients develop early Alzheimer's disease pathology with abundant cortical amyloid plaques, likely due to overproduction of the amyloid precursor protein (APP), which subsequently leads to amyloid β (Aβ) aggregation. This is reflected in cerebrospinal fluid (CSF) levels of the 42-amino acid long Aβ peptide (Aβ1-42), which are increased in young DS patients and decreases with age. However, it is unclear whether DS also affects other aspects of Aβ metabolism, including production of shorter C- and N-terminal truncated Aβ peptides, and production of peptides from the amyloid precursor-like protein 1 (APLP1), which is related to APP, and cleaved by the same enzymatic processing machinery. APLP1-derived peptides may be surrogate markers for Aβ1-42 production in the brain. Here, we used hybrid immunoaffinity-mass spectrometry and enzyme-linked immunosorbent assays to monitor several Aβ and APLP1 peptides in CSF from DS patients (n = 12) and healthy controls (n = 20). CSF levels of Aβ1-42 and three endogenous peptides derived from APLP1 (APL1β25, APL1β27 and APL1β28) were decreased in DS compared with controls, while a specific Aβ peptide, Aβ1-28, was increased in a majority of the DS individuals. This study indicates that DS causes previously unknown specific alterations of APP and APLP1 metabolism.
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden, erik.portelius@neuro.gu.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.forename: Mikko
authors.initials: M
authors.lastname: Hölttä
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Maria
authors.initials: M
authors.lastname: Bjerke
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Anni
authors.initials: A
authors.lastname: Westerlund
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
mesh_terms: D000328:Adult; D000367:Age Factors; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D004314:Down Syndrome / Q000134:cerebrospinal fluid*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D011499:Protein Processing, Post-Translational; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: C489697:APLP1 protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D010446:Peptide Fragments; C084358:amyloid beta-protein (1-28); C075222:amyloid beta-protein (1-42); D005341:Fibrinolysin
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