Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer’s Disease

Article type: Research Article

Authors: Tajeddinn, Walid^{a; *} | Persson, Torbjörn^a | Calvo-Garrido, Javier^a | Seed Ahmed, Mohammed^{a; b; c} | Maioli, Silvia^a | Vijayaraghavan, Swetha^a | Kazokoglu, Mehmet Selim^a | Parrado-Fernández, Cristina^a | Yoshitake, Takashi^d | Kehr, Jan^d | Francis, Paul^b | Winblad, Bengt^a | Höglund, Kina^{a; e} | Cedazo-Minguez, Angel^a | Aarsland, Dag^{a; f; g}

Affiliations: [a] Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden | [b] King’s College London, Wolfson Centre for Age Related-Diseases, London, UK | [c] Department of Physiology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan | [d] Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden | [e] Göteborg University Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Göteborg, Sweden | [f] Centre for Age- Related Medicine, Stavanger University Hospital, Stavanger, Norway | [g] Department of Neurology, Akershus University Hospital, Oslo, Norway

Correspondence: [*] Correspondence to: Dr. Walid Tajeddinn, MD, MSc, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Novum, Blickagången 6, 141 57 Huddinge, Sweden. Tel.: +46 883894; E-mail: [email protected].

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.

Keywords: 5-HT1B receptor, Alzheimer’s disease, APPswe, MAOA, p11, serotonin, SERT

DOI: 10.3233/JAD-160046

Journal: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 349-361, 2016