title: Genetic Variation in δ-Opioid Receptor Associates with Increased β- and γ-Secretase Activity in the Late Stages of Alzheimer's Disease.
abstract: The agonist-induced activation of human δ-opioid receptor (δOR) has been shown to increase β- (BACE1) and γ-secretase activities leading to increased production of amyloid-β (Aβ) peptide. We have recently shown that phenylalanine to cysteine substitution at amino acid 27 in δOR (δOR-Phe27Cys) increases amyloid-β protein precursor processing through altered endocytic trafficking. Also, a genetic meta-analysis of the δOR-Phe27Cys variation (rs1042114) in two independent Alzheimer's disease (AD) patient cohorts indicated that the heterozygosity of δOR-Phe27Cys increases the risk of AD. Here, we investigated α-, β-, and γ-secretase activities in human brain with respect to δOR-Phe27Cys variation in the temporal cortex of 71 subjects with varying degree of AD-related neurofibrillary pathology (Braak stages I-VI). As a result, a significant increase in β- (p = 0.03) and γ- (p = 0.01), but not α-secretase, activities was observed in late stage AD samples (Braak stages V-VI), which were heterozygous for δOR-Phe27Cys as compared to the δOR-Phe27 and δOR-Cys27 homozygotes. The augmented β-secretase activity was not associated with increased mRNA expression or protein levels of BACE1 in the late stage AD patients, who were heterozygous for the δOR-Phe27Cys variation. These findings suggest that δOR-Phe27Cys variation modulates β- and γ-secretase activity in the late stages of AD likely via post-translational mechanisms other than alterations in the mRNA or protein levels of BACE1, or, in the expression of γ-secretase complex components.
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.|Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Sarajärvi
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.|Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Marttinen
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.|Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Natunen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Kauppinen
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.|Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Petra
authors.initials: P
authors.lastname: Mäkinen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Helisalmi
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.|Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Marjo
authors.initials: M
authors.lastname: Laitinen
authors.affiliation: Department of Pathology, Kuopio University Hospital, Kuopio, Finland.|Institute of Clinical Medicine - Pathology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Rauramaa
authors.affiliation: Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland and Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
authors.affiliation: Medical Research Center Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland.
authors.forename: Ulla
authors.initials: U
authors.lastname: Petäjä-Repo
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.|Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.|Department of Neurobiology, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.|Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.|Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002908:Chronic Disease; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000235:genetics*; D013702:Temporal Lobe / Q000201:enzymology / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C529706:OPRD1 protein, human; C469349:PSENEN protein, human; D010446:Peptide Fragments; D012333:RNA, Messenger; D017465:Receptors, Opioid, delta; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer disease; amyloid-β; amyloid-β protein precursor; β-secretase; γ-secretase; δ-opioid receptor