title: DL0410 can reverse cognitive impairment, synaptic loss and reduce plaque load in APP/PS1 transgenic mice.
abstract: Cholinesterase inhibitors are first-line therapy for Alzheimer's disease (AD). DL0410 is an AChE/BuChE dual inhibitor with a novel new structural scaffold. It has been demonstrated that DL0410 could improve memory deficits in both Aβ1-42-induced and scopolamine-induced amnesia in mice. In the present study, the therapeutic effect of DL0410 and its action mechanism were investigated in APP/PS1 transgenic mice. Six-month old APP/PS1 transgenic mice were orally administered with DL0410 (3, 10, 30 mg/kg/day). After 60 days, several behavioural tests, including the Morris water maze and step-down tests, were used to investigate the effects of DL0410 on mice behaviours. All the behavioural experimental results showed that DL0410 significantly ameliorated memory deficits. Meanwhile, DL0410 attenuated neural cell damage and reduced senile plaques significantly in the hippocampus of APP/PS1 transgenic mice. In addition, DL0410 significantly decreased Aβ plaques, while increasing the number of synapses and the thickness of PSD in the hippocampus. We also found DL0410 decreased the expression of APP, NMDAR1B and the phosphorylation level of NMDAR2B, and increased the phosphorylation level of CAMKII and the expression of PSD-95. In this study, the results of behavioural tests demonstrated for the first time that DL0410 could improve learning and memory dysfunction in APP/PS1 transgenic mice. The mechanism of its beneficial effects might be related to cholinesterase inhibition, Aβ plaques inhibition, improvement of synapse loss by regulating of expression of proteins related to synapses. As a result, DL0410 could be considered as a candidate drug for the therapy of AD.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Jining No. 1 People's Hospital in Shandong Province, Jining 272011, China.
authors.forename: Ran-Yao
authors.initials: RY
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Xiao-Cong
authors.initials: XC
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Shou-Bao
authors.initials: SB
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Jian-Song
authors.initials: JS
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China. Electronic address: liuailin@imm.ac.cn.
authors.forename: Ai-Lin
authors.initials: AL
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: ws@imm.ac.cn.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China. Electronic address: dugh@imm.ac.cn.
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Du
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000097:blood; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy* / Q000473:pathology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D051528:Guanylate Kinases / Q000096:biosynthesis; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000378:metabolism; D057907:Post-Synaptic Density / Q000187:drug effects / Q000648:ultrastructure; D053764:Presenilin-1 / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000473:pathology*
chemical_list: D000110:Acetylcholinesterase; D016564:Amyloid beta-Protein Precursor; D002091:Butyrylcholinesterase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002800:Cholinesterase Inhibitors; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D008565:Membrane Proteins; D053764:Presenilin-1; D016194:Receptors, N-Methyl-D-Aspartate; C501447:Dlg4 protein, mouse; C121001:NR2B NMDA receptor
keywords: Alzheimer's disease; Amyloid β; Cholinesterase inhibitor; DL0410; Senile plaque; Synapse