Serotonin 6 receptor controls Alzheimer's disease and depression

Hyung-Mun Yun; Kyung-Ran Park; Eun-Cheol Kim; Sanghyeon Kim; Jin Tae Hong

doi:10.18632/oncotarget.5777

Serotonin 6 receptor controls Alzheimer's disease and depression

Oncotarget. 2015 Sep 29;6(29):26716-28. doi: 10.18632/oncotarget.5777.

Authors

Hyung-Mun Yun¹, Kyung-Ran Park², Eun-Cheol Kim¹, Sanghyeon Kim³, Jin Tae Hong⁴

Affiliations

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 Stanley Brain Research Laboratory, Stanley Medical Research Institute, Rockville, MD, USA.
⁴ College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Republic of Korea.

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-HT6R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT6R function between two diseases was poorly defined. In the present study, we found that a 5-HT6R 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-HT6R between AD and depression.

Keywords: 5-HT6R; APBA1/2; Alzheimer’s disease; depression; serotonin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Alzheimer Disease / diagnosis
Alzheimer Disease / drug therapy
Alzheimer Disease / genetics*
Amyloid / chemistry
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / chemistry*
Animals
Astrocytes / cytology
Astrocytes / metabolism
Behavior, Animal
Brain / drug effects
Brain / pathology
Cadherins / metabolism
Carrier Proteins / metabolism
Cognition Disorders / metabolism
Depression / diagnosis
Depression / genetics*
Disease Models, Animal
Fluoxetine / chemistry
Gene Expression Regulation*
Humans
Inflammation
Male
Maze Learning
Memory Disorders / drug therapy
Mice
Mice, Inbred ICR
Microglia / metabolism
Nerve Tissue Proteins / metabolism
Oligonucleotide Array Sequence Analysis
Peptide Fragments / chemistry*
Receptors, Serotonin / genetics*
Receptors, Serotonin / metabolism*
Sequence Analysis, RNA
Serotonergic Neurons
Serotonin Antagonists / chemistry*
Serotonin and Noradrenaline Reuptake Inhibitors / chemistry

Substances

APBA1 protein, human
APBA2 protein, human
Adaptor Proteins, Signal Transducing
Amyloid
Amyloid beta-Peptides
Apba1 protein, mouse
Apba2 protein, mouse
Cadherins
Carrier Proteins
Nerve Tissue Proteins
Peptide Fragments
Receptors, Serotonin
Serotonin Antagonists
Serotonin and Noradrenaline Reuptake Inhibitors
amyloid beta-protein (1-42)
serotonin 6 receptor
Fluoxetine
Amyloid Precursor Protein Secretases