Genetic Variation in δ-Opioid Receptor Associates with Increased β- and γ-Secretase Activity in the Late Stages of Alzheimer’s Disease

Article type: Research Article

Authors: Sarajärvi, Timo^{a; b} | Marttinen, Mikael^{a; b} | Natunen, Teemu^{a; b} | Kauppinen, Tarja^b | Mäkinen, Petra^{a; b} | Helisalmi, Seppo^b | Laitinen, Marjo^{b; h} | Rauramaa, Tuomas^{c; d} | Leinonen, Ville^e | Petäjä-Repo, Ulla^f | Soininen, Hilkka^{b; h} | Haapasalo, Annakaisa^{b; g; 1} | Hiltunen, Mikko^{a; b; h; *; 1}

Affiliations: [a] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland | [b] Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland | [c] Department of Pathology, Kuopio University Hospital, Kuopio, Finland | [d] Institute of Clinical Medicine – Pathology, University of Eastern Finland, Kuopio, Finland | [e] Institute of Clinical Medicine – Neurosurgery, University of Eastern Finland and Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland | [f] Medical Research Center Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland | [g] Department of Neurobiology, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland | [h] Department of Neurology, Kuopio University Hospital, Kuopio, Finland

Correspondence: [*] Correspondence to: Mikko Hiltunen, PhD, School of Medicine – Institute of Biomedicine, University of Eastern Finland,Yliopistonranta 1E, 70211 Kuopio, Finland. Tel.: +358 40 3552014; mikko.hiltunen@uef.fi

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer disease, amyloid-β, amyloid-β protein precursor, β-secretase, γ-secretase, δ-opioid receptor

DOI: 10.3233/JAD-150221

Journal: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 507-516, 2015