Hippocampus-specific deficiency in RNA editing of GluA2 in Alzheimer's disease

Adenosine to inosine (A-to-I) RNA editing is a base recoding process within precursor messenger RNA, catalyzed by members of the adenosine deaminase acting on RNA (ADAR) family. A notable example occurs at the Q/R site of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor subunit GluA2. Abnormally, low editing at this site leads to excessive calcium influx and cell death. We studied hippocampus and caudate samples from Alzheimer's disease (AD) patients and age-matched healthy controls, using direct sequencing and a high accuracy primer-extension technique to assess RNA editing at the Q/R GluA2 site. Both techniques revealed lower, more variable RNA editing in AD, specific to the hippocampus and the GluA2 site. Deficient editing also characterized the hippocampus of apolipoprotein ε4 allele carriers, regardless of clinical diagnosis. In AD, messenger RNA expression of neuronal markers was decreased in the hippocampus, and expression of the Q/R-site editing enzyme ADAR2 was decreased in caudate. These findings provide a link between neurodegenerative processes and deficient RNA editing of the GluA2 Q/R site, and may contribute to both diagnosis and treatment of AD.

[1]  S. Gershon,et al.  Is the neuronal basis of Alzheimer's disease cholinergic or glutamatergic? , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  D. Feldmeyer,et al.  Neurological dysfunctions in mice expressing different levels of the Q/R site–unedited AMPAR subunit GluR–B , 1999, Nature Neuroscience.

[3]  R. Dingledine,et al.  Identification of a site in glutamate receptor subunits that controls calcium permeability , 1991, Science.

[4]  G. Schellenberg,et al.  Apolipoprotein E genotype and Alzheimer's disease. , 1993, Lancet.

[5]  Michael I. Miller,et al.  Changes in hippocampal volume and shape across time distinguish dementia of the Alzheimer type from healthy aging☆ , 2003, NeuroImage.

[6]  T. Hemnani,et al.  Alzheimer’s disease pathogenesis and therapeutic interventions , 2004, Journal of Clinical Neuroscience.

[7]  K. Nishikura,et al.  A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. , 2000, RNA.

[8]  R. Dingledine,et al.  AMPA receptors: molecular and functional diversity. , 1998, Progress in brain research.

[9]  A. Barbon,et al.  Glutamate receptor RNA editing: a molecular analysis of GluR2, GluR5 and GluR6 in human brain tissues and in NT2 cells following in vitro neural differentiation. , 2003, Brain Research. Molecular Brain Research.

[10]  P. Davies,et al.  The Loss of GluR2(3) Immunoreactivity Precedes Neurofibrillary Tangle Formation in the Entorhinal Cortex and Hippocampus of Alzheimer Brains , 1997, Journal of neuropathology and experimental neurology.

[11]  D. Feldmeyer,et al.  Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2 , 2000, Nature.

[12]  M. Mattson.  Pathways towards and away from Alzheimer's disease , 2004, Nature.

[13]  S. Akbarian,et al.  Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer's disease, Huntington's disease and schizophrenia , 1995, Brain Research.

[14]  J. Poirier,et al.  AMPA receptor regulation and LTP in the hippocampus of young and aged apolipoprotein E-deficient mice , 2001, Neurobiology of Aging.

[15]  Y. Liu,et al.  ADAR2-dependent RNA editing of GluR2 is involved in thiamine deficiency-induced alteration of calcium dynamics , 2010, Molecular Neurodegeneration.

[16]  Edgar Erdfelder,et al.  G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences , 2007, Behavior research methods.

[17]  A. D. Roses,et al.  Association of apolipoprotein E allele €4 with late-onset familial and sporadic Alzheimer’s disease , 2006 .

[18]  A. Nagler,et al.  A new MALDI-TOF-based assay for monitoring JAK2 V617F mutation level in patients undergoing allogeneic stem cell transplantation (allo SCT) for classic myeloproliferative disorders (MPD). , 2008, Leukemia research.

[19]  C. Jack,et al.  11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. , 2008, Brain : a journal of neurology.

[20]  Ichiro Kanazawa,et al.  Glutamate receptors: RNA editing and death of motor neurons , 2004, Nature.

[21]  Allan R. Jones,et al.  An anatomically comprehensive atlas of the adult human brain transcriptome , 2012, Nature.

[22]  K. Nishikura,et al.  RNA Binding-independent Dimerization of Adenosine Deaminases Acting on RNA and Dominant Negative Effects of Nonfunctional Subunits on Dimer Functions* , 2007, Journal of Biological Chemistry.

[23]  J. Eldor.  Immediate intracardiac adrenaline injection in asystole , 1993, The Lancet.

[24]  A. Cedazo-Mínguez,et al.  Apolipoprotein E and Alzheimer's disease: molecular mechanisms and therapeutic opportunities , 2007, Journal of cellular and molecular medicine.

[25]  B. Sakmann,et al.  Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS , 1995, Neuron.

[26]  S. B. Kater,et al.  Intrinsic factors in the selective vulnerability of hippocampal pyramidal neurons. , 1989, Progress in clinical and biological research.

[27]  Erez Y. Levanon,et al.  Evolutionarily conserved human targets of adenosine to inosine RNA editing , 2005, Nucleic acids research.

[28]  S. Tsuji,et al.  Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons , 2012, Neurobiology of Disease.

[29]  R. Zukin,et al.  Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death , 2007, Trends in Neurosciences.

[30]  T. Mikkelsen,et al.  Altered adenosine-to-inosine RNA editing in human cancer. , 2007, Genome research.

[31]  R. Emeson,et al.  Altered RNA Editing in Mice Lacking ADAR2 Autoregulation , 2006, Molecular and Cellular Biology.

[32]  B. Sakmann,et al.  Coincidence detection and changes of synaptic efficacy in spiny stellate neurons in rat barrel cortex , 1999, Nature Neuroscience.

[33]  M. Ball,et al.  Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: Transcription and neurotrophic factor down‐regulation and up‐regulation of apoptotic and pro‐inflammatory signaling , 2002, Journal of neuroscience research.

[34]  C. Cantor,et al.  A single nucleotide polymorphism based approach for the identification and characterization of gene expression modulation using MassARRAY. , 2005, Mutation research.

[35]  H. Braak,et al.  Staging of alzheimer's disease-related neurofibrillary changes , 1995, Neurobiology of Aging.

[36]  K. Nishikura,et al.  ADAR gene family and A-to-I RNA editing: diverse roles in posttranscriptional gene regulation. , 2005, Progress in nucleic acid research and molecular biology.

[37]  P. L. Peng,et al.  ADAR2-Dependent RNA Editing of AMPA Receptor Subunit GluR2 Determines Vulnerability of Neurons in Forebrain Ischemia , 2006, Neuron.

[38]  Y. Nishimoto,et al.  Newly identified ADAR-mediated A-to-I editing positions as a tool for ALS research , 2008, RNA biology.

[39]  John M. Murray,et al.  Requirement of Dimerization for RNA Editing Activity of Adenosine Deaminases Acting on RNA* , 2003, The Journal of Biological Chemistry.

[40]  Jochen C. Hartner,et al.  Specificity of ADAR-mediated RNA editing in newly identified targets. , 2008, RNA.

[41]  Dirk Feldmeyer,et al.  Early-Onset Epilepsy and Postnatal Lethality Associated with an Editing-Deficient GluR-B Allele in Mice , 1995, Science.

[42]  S. Gandy,et al.  Differential preservation of AMPA receptor subunits in the hippocampi of Alzheimer's disease patients according to Braak stage , 2004, Experimental Neurology.

[43]  S. Heinemann,et al.  Ca2+ permeability of KA-AMPA--gated glutamate receptor channels depends on subunit composition , 1991, Science.

[44]  T. Dawson,et al.  Regulation of alternative splicing by RNA editing , 1999, Nature.

[45]  D. Mann,et al.  Pyramidal nerve cell loss in Alzheimer's disease. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[46]  B. Sakmann,et al.  Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit , 1992, Neuron.

[47]  Nick C Fox,et al.  Presymptomatic hippocampal atrophy in Alzheimer's disease. A longitudinal MRI study. , 1996, Brain : a journal of neurology.

[48]  J. Herz,et al.  ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling , 2010, Proceedings of the National Academy of Sciences.

[49]  P. Jonas,et al.  Molecular mechanisms controlling calcium entry through AMPA-type glutamate receptor channels , 1995, Neuron.

[50]  Y. Kawahara,et al.  Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis , 2005, Journal of Molecular Medicine.

[51]  Brenda L Bass,et al.  RNA editing by adenosine deaminases that act on RNA. , 2002, Annual review of biochemistry.