title: Mechanism of depression as a risk factor in the development of Alzheimer's disease: the function of AQP4 and the glymphatic system.
abstract: Many studies have indicated that a history of depression increases the risk of developing Alzheimer's disease (AD); however, the potential pathogenestic mechanism by which depression functions as a high risk factor for AD remains unknown. Recently, a "cerebral lymphatic system" referred to as "glymphatic system" has been demonstrated to be responsible for neuronal extracellular waste protein clearance via a paravascular pathway. However, the function of glymphatic pathway has not been determined in depressive disorders.
  
  
  
  The present study used an animal model of chronic unpredictable mild stress (CUMS) to determine the function of glymphatic pathway by using fluorescence tracers. Immunohistochemistry was used to assess the accumulation of endogenous mouse and exogenous human amyloid beta 42 (Aβ42) in CUMS-treated mice with or without treatment with antidepressant fluoxetine.
  
  
  
  Glymphatic pathway circulation was impaired in mice treated with CUMS; moreover, glymphatic pathway dysfunction suppressed Aβ42 metabolism, because the accumulation of endogenous and exogenous Aβ42 was increased in the brains of the CUMS-treated mice. However, treatment with fluoxetine reversed these destructive effects of CUMS on glymphatic system. In anhedonic mice, the expression of the water channel aquaporin 4 (AQP4), a factor in glymphatic pathway dysfunction, was down-regulated in cortex and hippocampus.
  
  
  
  The dysfunction of glymphatic system suggested why a history of depression may be a strong risk factor for AD in anhedonic mice. We hope our study will contribute to an understanding of the risk mechanism of depressive disorder in the development of AD and the mechanisms of antidepressant therapies in AD.
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, No. 77, Puhe Street, Shenbei District, Shenyang, 110177, People's Republic of China.|Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Xia
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, No. 77, Puhe Street, Shenbei District, Shenyang, 110177, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, No. 77, Puhe Street, Shenbei District, Shenyang, 110177, People's Republic of China.|Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Guangfeng
authors.initials: G
authors.lastname: Sun
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, No. 77, Puhe Street, Shenbei District, Shenyang, 110177, People's Republic of China.|Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Qi
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, No. 77, Puhe Street, Shenbei District, Shenyang, 110177, People's Republic of China. baomanli1226@yahoo.com.|Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, People's Republic of China. baomanli1226@yahoo.com.
authors.forename: Baoman
authors.initials: B
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D059445:Anhedonia; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D051401:Aquaporin 4 / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003866:Depressive Disorder / Q000378:metabolism; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008208:Lymphatic System / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism*; D012307:Risk Factors; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000928:Antidepressive Agents; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005473:Fluoxetine
keywords: Alzheimer’s disease; Amyloid beta 42; Chronic unpredictable mild stress; Depression; Glymphatic pathway