title: RPS23RG1 reduces Aβ oligomer-induced synaptic and cognitive deficits.
abstract: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is generally believed that β-amyloidogenesis, tau-hyperphosphorylation, and synaptic loss underlie cognitive decline in AD. Rps23rg1, a functional retroposed mouse gene, has been shown to reduce Alzheimer's β-amyloid (Aβ) production and tau phosphorylation. In this study, we have identified its human homolog, and demonstrated that RPS23RG1 regulates synaptic plasticity, thus counteracting Aβ oligomer (oAβ)-induced cognitive deficits in mice. The level of RPS23RG1 mRNA is significantly lower in the brains of AD compared to non-AD patients, suggesting its potential role in the pathogenesis of the disease. Similar to its mouse counterpart, human RPS23RG1 interacts with adenylate cyclase, activating PKA/CREB, and inhibiting GSK-3. Furthermore, we show that human RPS23RG1 promotes synaptic plasticity and offsets oAβ-induced synaptic loss in a PKA-dependent manner in cultured primary neurons. Overexpression of Rps23rg1 in transgenic mice consistently prevented oAβ-induced PKA inactivation, synaptic deficits, suppression of long-term potentiation, and cognitive impairment as compared to wild type littermates. Our study demonstrates that RPS23RG1 may reduce the occurrence of key elements of AD pathology and enhance synaptic functions to counteract oAβ-induced synaptic and cognitive deficits in AD.
authors.affiliation: Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, China.|Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Yaomin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Functional Genetics, Inc., Gaithersburg, MD, USA.
authors.forename: Wubo
authors.initials: W
authors.lastname: Li
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Hedieh
authors.initials: H
authors.lastname: Badie
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Jian
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Huang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Stanley N
authors.initials: SN
authors.lastname: Cohen
authors.affiliation: Functional Genetics, Inc., Gaithersburg, MD, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Li
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.|Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen 361102, China.
authors.forename: Yun-Wu
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, China.
authors.forename: Huanmin
authors.initials: H
authors.lastname: Luo
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Shichun
authors.initials: S
authors.lastname: Tu
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D003001:Cloning, Molecular; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D017774:Long-Term Potentiation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D012269:Ribosomal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D066329:Protein Aggregates; D012333:RNA, Messenger; C484213:RPS23 protein, human; C545338:RPS23R1 protein, mouse; D012269:Ribosomal Proteins; D016875:tau Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8