title: Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer's Disease.
abstract: Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer's disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Walid
authors.initials: W
authors.lastname: Tajeddinn
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Persson
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Javier
authors.initials: J
authors.lastname: Calvo-Garrido
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.|King's College London, Wolfson Centre for Age Related-Diseases, London, UK.|Department of Physiology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Seed Ahmed
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maioli
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Swetha
authors.initials: S
authors.lastname: Vijayaraghavan
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Mehmet Selim
authors.initials: MS
authors.lastname: Kazokoglu
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Cristina
authors.initials: C
authors.lastname: Parrado-Fernández
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshitake
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Kehr
authors.affiliation: King's College London, Wolfson Centre for Age Related-Diseases, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Francis
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.|Göteborg University Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Göteborg, Sweden.
authors.forename: Kina
authors.initials: K
authors.lastname: Höglund
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Angel
authors.initials: A
authors.lastname: Cedazo-Minguez
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.|Centre for Age- Related Medicine, Stavanger University Hospital, Stavanger, Norway.|Department of Neurology, Akershus University Hospital, Oslo, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Aarsland
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D055664:Electrochemical Techniques; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010881:Piperidones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D018709:Statistics, Nonparametric; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D010881:Piperidones; D012333:RNA, Messenger; D044302:Receptor, Serotonin, 5-HT1B; C108518:SB 22489G; C493230:SLC6A4 protein, human; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D013141:Spiro Compounds; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: 5-HT1B receptor; APPswe; Alzheimer’s disease; MAOA; SERT; p11; serotonin