Serotonin 6 receptor controls alzheimer’s disease and depression

Abstract

// Hyung-Mun Yun 1,* , Kyung-Ran Park 2,* , Eun-Cheol Kim 1 , Sanghyeon Kim 4 and Jin Tae Hong 3 1 Department of Maxillofacial Tissue Regeneration, School of Dentistry and Research Center for Tooth and Periodontal Regeneration (MRC), Kyung Hee University, Seoul, Republic of Korea 2 Department of Oral & Maxillofacial Regeneration, Kyung Hee University, Seoul, Republic of Korea 3 College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Republic of Korea 4 Stanley Brain Research Laboratory, Stanley Medical Research Institute, Rockville, MD, USA * These authors have contributed equally to this work Correspondence to: Jin Tae Hong, email: // Sanghyeon Kim, email: // Keywords : 5-HT6R, serotonin, APBA1/2, alzheimer’s disease, depression Received : August 19, 2015 Accepted : August 29, 2015 Published : September 22, 2015 Abstract Alzheimer’s disease (AD) and depression in late life are one of the most severe health problems in the world disorders. Serotonin 6 receptor (5-HT 6 R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT 6 R function between two diseases was poorly defined. In the present study, we found that a 5-HT 6 R antagonist, SB271036 rescued memory impairment by attenuating the generation of Aβ via the inhibition of γ-secretase activity and the inactivation of astrocytes and microglia in the AD mouse model. It was found that the reduction of serotonin level was significantly recovered by SB271036, which was mediated by an indirect regulation of serotonergic neurons via GABA. Selective serotonin reuptake inhibitor (SSRI), fluoxetine significantly improved cognitive impairment and behavioral changes. In human brain of depression patients, we then identified the potential genes, amyloid beta (A4) precursor protein-binding, family A, member 2 (APBA2), well known AD modulators by integrating datasets from neuropathology, microarray, and RNA seq. studies with correlation analysis tools. And also, it was demonstrated in mouse models and patients of AD. These data indicate functional network of 5-HT 6 R between AD and depression.