Sarajärvi Timo, Marttinen Mikael, Natunen Teemu, Kauppinen Tarja, Mäkinen Petra, Helisalmi Seppo, Laitinen Marjo, Rauramaa Tuomas, Leinonen Ville, Petäjä-Repo Ulla, Soininen Hilkka, Haapasalo Annakaisa, Hiltunen Mikko
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
J Alzheimers Dis. 2015;48(2):507-16. doi: 10.3233/JAD-150221.
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.
激动剂诱导的人δ-阿片受体（δOR）激活已被证明会增加β-（β-分泌酶1，BACE1）和γ-分泌酶活性，导致淀粉样β（Aβ）肽生成增加。我们最近发现，δOR第27位氨基酸由苯丙氨酸突变为半胱氨酸（δOR-Phe27Cys）会通过改变内吞运输增加淀粉样β蛋白前体的加工。此外，对两个独立的阿尔茨海默病（AD）患者队列中δOR-Phe27Cys变异（rs1042114）的基因荟萃分析表明，δOR-Phe27Cys杂合性会增加AD风险。在此，我们针对71名具有不同程度AD相关神经原纤维病变（Braak分期I-VI）的受试者颞叶皮质中δOR-Phe27Cys变异，研究了人脑α-、β-和γ-分泌酶活性。结果发现，与δOR-Phe27和δOR-Cys27纯合子相比，晚期AD样本（Braak分期V-VI）中，δOR-Phe27Cys杂合子的β-（p = 0.03）和γ-（p = 0.01）分泌酶活性显著增加，但α-分泌酶活性未增加。晚期AD患者中，δOR-Phe27Cys变异为杂合子，其增强的β-分泌酶活性与BACE1的mRNA表达增加或蛋白质水平升高无关。这些发现表明，δOR-Phe27Cys变异可能通过翻译后机制而非BACE1的mRNA或蛋白质水平改变，或γ-分泌酶复合物成分的表达，在AD晚期调节β-和γ-分泌酶活性。
