title: Quetiapine attenuates glial activation and proinflammatory cytokines in APP/PS1 transgenic mice via inhibition of nuclear factor-κB pathway.
abstract: BACKGROUND
  In Alzheimer's disease, growing evidence has shown that uncontrolled glial activation and neuroinflammation may contribute independently to neurodegeneration. Antiinflammatory strategies might provide benefits for this devastating disease. The aims of the present study are to address the issue of whether glial activation and proinflammatory cytokine increases could be modulated by quetiapine in vivo and in vitro and to explore the underlying mechanism.
  
  
  METHODS
  Four-month-old amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic and nontransgenic mice were treated with quetiapine (5mg/kg/d) in drinking water for 8 months. Animal behaviors, total Aβ levels, and glial activation were evaluated by behavioral tests, enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot accordingly. Inflammatory cytokines and the nuclear factor kappa B pathway were analyzed in vivo and in vitro.
  
  
  RESULTS
  Quetiapine improves behavioral performance, marginally affects total Aβ40 and Aβ42 levels, attenuates glial activation, and reduces proinflammatory cytokines in APP/PS1 mice. Quetiapine suppresses Aβ1-42-induced activation of primary microglia by decresing proinflammatory cytokines. Quetiapine inhibits the activation of nuclear factor kappa B p65 pathway in both transgenic mice and primary microglia stimulated by Aβ1-42.
  
  
  CONCLUSIONS
  The antiinflammatory effects of quetiapine in Alzheimer's disease may be involved in the nuclear factor kappa B pathway. Quetiapine may be an efficacious and promising treatment for Alzheimer's disease targeting on neuroinflammation.
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).
authors.forename: Shenghua
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).
authors.forename: Ruoyang
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).
authors.forename: Victor
authors.initials: V
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).
authors.forename: Junhui
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).
authors.forename: Ruiguo
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).
authors.forename: Adrien
authors.initials: A
authors.lastname: Tempier
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).
authors.forename: Jue
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).
authors.forename: Jiming
authors.initials: J
authors.lastname: Kong
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He). xinmin@ualberta.ca.
authors.forename: Xin-Min
authors.initials: XM
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000378:metabolism*; D003987:Dibenzothiazepines / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D000069348:Quetiapine Fumarate; D021641:Recognition, Psychology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; D016207:Cytokines; D003987:Dibenzothiazepines; D016328:NF-kappa B; D053764:Presenilin-1; D000069348:Quetiapine Fumarate
keywords: NF-κB; astrocyte; microglia; neuroinflammation; quetiapine