title: Disrupted-in-Schizophrenia-1 Attenuates Amyloid-β Generation and Cognitive Deficits in APP/PS1 Transgenic Mice by Reduction of β-Site APP-Cleaving Enzyme 1 Levels.
abstract: Disrupted-in-Schizophrenia-1 (DISC1) is a genetic risk factor for a wide range of major mental disorders, including schizophrenia, major depression, and bipolar disorders. Recent reports suggest a potential role of DISC1 in the pathogenesis of Alzheimer's disease (AD), by referring to an interaction between DISC1 and amyloid precursor protein (APP), and to an association of a single-nucleotide polymorphism in a DISC1 intron and late onset of AD. However, the function of DISC1 in AD remains unknown. In this study, decreased levels of DISC1 were observed in the cortex and hippocampus of 8-month-old APP/PS1 transgenic mice, an animal model of AD. Overexpression of DISC1 reduced, whereas knockdown of DISC1 increased protein levels, but not mRNA levels of β-site APP-Cleaving Enzyme 1 (BACE1), a key enzyme in amyloid-β (Aβ) generation. Reduction of BACE1 protein levels by overexpression of DISC1 was accompanied by an accelerating decline rate of BACE1, and was blocked by the lysosomal inhibitor chloroquine, rather than proteasome inhibitor MG-132. Moreover, overexpression of DISC1 in the hippocampus with an adeno-associated virus reduced the levels of BACE1, soluble Aβ40/42, amyloid plaque density, and rescued cognitive deficits of APP/PS1 transgenic mice. These results indicate that DISC1 attenuates Aβ generation and cognitive deficits of APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1. Our findings provide new insights into the role of DISC1 in AD pathogenesis and link a potential function of DISC1 to the psychiatric symptoms of AD.
authors.affiliation: Affiliated Bayi Brain Hospital and Affiliated Beijing Military Hospital of Southern Medical University, Beijing, China.
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Deng
authors.affiliation: Affiliated Bayi Brain Hospital and Affiliated Beijing Military Hospital of Southern Medical University, Beijing, China.
authors.forename: Xing-Yu
authors.initials: XY
authors.lastname: Dong
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Affiliated Bayi Brain Hospital and Affiliated Beijing Military Hospital of Southern Medical University, Beijing, China.
authors.forename: Zhao-Tao
authors.initials: ZT
authors.lastname: Wang
authors.affiliation: Affiliated Bayi Brain Hospital and Affiliated Beijing Military Hospital of Southern Medical University, Beijing, China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
authors.affiliation: Affiliated Bayi Brain Hospital and Affiliated Beijing Military Hospital of Southern Medical University, Beijing, China.
authors.forename: Wei-Qiang
authors.initials: WQ
authors.lastname: Jia
authors.affiliation: Affiliated Bayi Brain Hospital and Affiliated Beijing Military Hospital of Southern Medical University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Neuroscience, Shantou University Medical College, Shantou, China.|Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA.
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
authors.forename: Quan-Hong
authors.initials: QH
authors.lastname: Ma
authors.affiliation: Affiliated Bayi Brain Hospital and Affiliated Beijing Military Hospital of Southern Medical University, Beijing, China.
authors.forename: Ru-Xiang
authors.initials: RX
authors.lastname: Xu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000378:metabolism*; D003412:Cricetulus; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; D007976:Leupeptins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D061988:Proteasome Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde