title: Clozapine Improves Memory Impairment and Reduces Aβ Level in the Tg-APPswe/PS1dE9 Mouse Model of Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is a progressive degenerative condition. In order to treat AD, the use of a "drug repositioning" or "repurposing" approach with potential disease-modifying compounds has been increased. The new generation antipsychotics are commonly used in AD and other dementias for the treatment of psychosis and behavioral symptoms, and several animal models have shown the effects of these potential disease-modifying compounds. In this study, we examined whether long-term clozapine treatment could reduce amyloid beta (Aβ) deposition and cognitive impairment in transgenic mice of AD, Tg-APPswe/PS1dE9. AD mice were fed clozapine at 20 mg/kg/day for 3 months from 4.5 months of age. Intake of clozapine improved the Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of AD mice. Clozapine upregulated Trk, brain-derived neurotrophic factor, cyclin-dependent kinase-5, and p35 in the cortex and hippocampus of AD mice and activated AMP-activated protein kinase (AMPK). As a downstream effector of AMPK, beta-secretase expression was decreased by clozapine administration. Moreover, clozapine-phosphorylated synapsin I at Ser9 and Ser549 sites in the hippocampus and cortex of AD mice, which may be involved in synaptic strength. This study suggests that as one of candidate for multi-target approach of AD treatment, clozapine is proposed as a therapeutic drug for treatment of AD patients.
authors.affiliation: Department of Biomedical Engineering, Dongguk University, Gyeonggi-do, 10326, Republic of Korea.
authors.forename: Yura
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Dongguk University Research Institute of Bio-Medi Integration, Sangyoung-Bio, Biomedi-Campus, Dongguk-ro 32, Goyang-si, Gyeonggi-do, 10326, Republic of Korea.
authors.forename: Ha Jin
authors.initials: HJ
authors.lastname: Jeong
authors.affiliation: Department of Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeongju, 38066, Republic of Korea.
authors.forename: Quan Feng
authors.initials: QF
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, Dongguk University, Gyeonggi-do, 10326, Republic of Korea.
authors.forename: Seung Tack
authors.initials: ST
authors.lastname: Oh
authors.affiliation: Department of Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeongju, 38066, Republic of Korea.
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Koo
authors.affiliation: Department of Child Psychiatry, National Center for Child and Adolescent Psychiatry, Seoul National Hospital, Seoul, 04933, Republic of Korea.
authors.forename: Yeni
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Neuropsychiatry, Dongguk University International Hospital, Dongguk University Medical School, Gyeonggi-do, 10326, Republic of Korea.
authors.forename: In-Won
authors.initials: IW
authors.lastname: Chung
authors.affiliation: Department of Neuropsychiatry, Dongguk University International Hospital, Dongguk University Medical School, Gyeonggi-do, 10326, Republic of Korea. kys@snu.ac.kr.
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Dongguk University Research Institute of Bio-Medi Integration, Sangyoung-Bio, Biomedi-Campus, Dongguk-ro 32, Goyang-si, Gyeonggi-do, 10326, Republic of Korea. jsong0304@dongguk.edu.
authors.forename: Songhee
authors.initials: S
authors.lastname: Jeon
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C580804:presenilin 1, mouse; D003024:Clozapine
keywords: AMPK; Alzheimer’s disease; BACE; CDK5; Clozapine; Synapsin