Genetic Variation in δ-Opioid Receptor Associates with Increased β- and γ-Secretase Activity in the Late Stages of Alzheimer's Disease
| Autor: | Seppo Helisalmi, Timo Sarajärvi, Hilkka Soininen, Ulla E. Petäjä-Repo, Petra Mäkinen, Tarja Kauppinen, Mikko Hiltunen, Annakaisa Haapasalo, Teemu Natunen, Tuomas Rauramaa, Mikael Marttinen, Ville Leinonen, Marjo Laitinen |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Biology Alzheimer Disease Internal medicine Receptors Opioid delta Genetic variation medicine Aspartic Acid Endopeptidases Humans RNA Messenger Receptor Protein precursor Temporal cortex Aged 80 and over Messenger RNA Amyloid beta-Peptides General Neuroscience Genetic Variation Membrane Proteins Neurofibrillary Tangles General Medicine Human brain medicine.disease Peptide Fragments Temporal Lobe Psychiatry and Mental health Clinical Psychology medicine.anatomical_structure Endocrinology Biochemistry Chronic Disease biology.protein Female Geriatrics and Gerontology Alzheimer's disease Amyloid Precursor Protein Secretases Amyloid precursor protein secretase |
| Zdroj: | Journal of Alzheimer's disease : JAD. 48(2) |
| ISSN: | 1875-8908 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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