Ampa/kainate receptor gene expression in normal and alzheimer's disease hippocampus

Alzheimer's disease is a progressive dementia characterized by pronounced degeneration of certain populations of neurons in the hippocampus and cerebral cortex of the brain. One theory is that glutamate receptor-mediated toxicity plays a role in cell loss associated with Alzheimer's disease. We used in situ hybridization to examine GluR1, GluR2, and GluR3 messengerRNAs (encoding alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate receptor subunits) in sections of autopsy samples of Alzheimer's disease brains and age-, sex-, and post-mortem delay-matched brains from non-demented (control) subjects. GluR1 and GluR2 exhibited a heterogeneous distribution in control brain. GluR1 was expressed in granule cells of the dentate gyrus, in pyramidal cells of the CA1 and CA3 hippocampal subfields and in neurons of the subiculum and entorhinal cortex. GluR2 mRNA was at high density in the dentate gyrus and in CA3, but was at low density in CA1, subiculum, and entorhinal cortex. GluR3 hybridization was at very low levels but selectively localized to the dentate gyrus and CA3. In cerebellum, GluR1 was found in granule and Purkinje cell layers. In sections from Alzheimer's disease brain, a high degree of intersubject variability was observed: some samples showed markedly reduced GluR1 mRNA levels in dentate gyrus, CA1 and CA3 relative to controls; others showed no changes. Microscopic observation of emulsion-dipped sections revealed that the reduction of GluR1 seen in the dentate gyrus and CA3 of some Alzheimer's disease subjects was not due to cell loss.(ABSTRACT TRUNCATED AT 250 WORDS)

[1]  A. Young,et al.  Excitatory amino acids and Alzheimer's disease , 1989, Neurobiology of Aging.

[2]  B. Sakmann,et al.  Structural determinants of ion flow through recombinant glutamate receptor channels , 1991, Science.

[3]  M. Mattson,et al.  beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  B. Kjessler.  CANCER OF THE LARYNX. , 1964, Lancet.

[5]  D. Graham,et al.  Glutamate metabotropic and AMPA binding sites are reduced in Alzheimer's disease: an autoradiographic study of the hippocampus , 1991, Brain Research.

[6]  G. V. Van Hoesen,et al.  Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. , 1984, Science.

[7]  C. Cotman,et al.  Aggregation-related toxicity of synthetic beta-amyloid protein in hippocampal cultures. , 1991, European journal of pharmacology.

[8]  D. Selkoe.  The molecular pathology of Alzheimer's disease , 1991, Neuron.

[9]  J. Penney,et al.  Dementia of the Alzheimer's Type: Changes in Hippocampal L‐[3H]Glutamate Binding , 1987, Journal of neurochemistry.

[10]  Paul J. Harrison,et al.  Decreased hippocampal expression of a glutamate receptor gene in schizophrenia , 1991, The Lancet.

[11]  C. Cotman,et al.  β-Amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage , 1990, Brain Research.

[12]  J. Garthwaite,et al.  Excitatory amino acid neurotoxicity and neurodegenerative disease. , 1990, Trends in pharmacological sciences.

[13]  John Hardy,et al.  Region-specific loss of glutamate innervation in Alzheimer's disease , 1987, Neuroscience Letters.

[14]  L. Hood,et al.  Molecular cloning and chromosomal localization of one of the human glutamate receptor genes. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Z. Khachaturian.  Diagnosis of Alzheimer's disease. , 1985, Archives of neurology.

[16]  Paul J. Harrison,et al.  In situ hybridization histochemistry and the study of gene expression in the human brain , 1990, Progress in Neurobiology.

[17]  D. Choi,et al.  Glutamate neurotoxicity and diseases of the nervous system , 1988, Neuron.

[18]  S. Heinemann,et al.  Cloning by functional expression of a member of the glutamate receptor family , 1989, Nature.

[19]  P. Davies,et al.  SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE , 1976, The Lancet.

[20]  M. Yamazaki,et al.  Functional expression from cloned cDNAs of glutamate receptor species responsive to kainate and quisqualate , 1990, FEBS letters.

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

[22]  D. Kirschner,et al.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. , 1990, Science.

[23]  R. DeTeresa,et al.  Some morphometric aspects of the brain in senile dementia of the alzheimer type , 1981, Annals of neurology.

[24]  F. Fonnum.  Glutamate: A Neurotransmitter in Mammalian Brain , 1984, Journal of neurochemistry.

[25]  M. Beal,et al.  An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Hardy,et al.  Alzheimer's disease: the amyloid cascade hypothesis. , 1992, Science.

[27]  M. Mattson.  Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons , 1990, Neuron.

[28]  C. Cotman,et al.  Hippocampal excitatory amino acid receptors in elderly, normal individuals and those with Alzheimer's disease: Non-N-methyl-d-aspartate receptors , 1992, Neuroscience.

[29]  S. Heinemann,et al.  Molecular cloning and functional expression of glutamate receptor subunit genes. , 1990, Science.

[30]  J. Deakin,et al.  Regional changes in [3H]d-aspartate and [3H]TCP binding sites in Alzheimer's disease brains , 1988, Brain Research.

[31]  J. Miller,et al.  Effect of pre- and postmortem variables on specific mRNA levels in human brain. , 1991, Brain research. Molecular brain research.

[32]  A. F. Schinder,et al.  Molecular cloning, chromosomal mapping, and functional expression of human brain glutamate receptors. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[33]  R. Faull,et al.  Alzheimer's disease: Changes in hippocampal N-methyl-d-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors—an autoradiographic study , 1990, Neuroscience.

[34]  U. Boni,et al.  Controlled induction of paired helical filaments of the Alzheimer type in cultured human neurons, by glutamate and aspartate , 1985, Journal of the Neurological Sciences.

[35]  B. Sakmann,et al.  Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. , 1990, Science.

[36]  E. Rojas,et al.  Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[37]  D L Price,et al.  Alzheimer's disease: a disorder of cortical cholinergic innervation. , 1983, Science.

[38]  Paul J. Harrison,et al.  Distribution of a kainate/AMPA receptor mRNA in normal and Alzheimer brain. , 1990, Neuroreport.

[39]  R. Katzman.,et al.  Advances in Alzheimer's disease , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  J. Olney,et al.  Excitotoxic amino acids and neuropsychiatric disorders. , 1990, Annual review of pharmacology and toxicology.

[41]  G. V. Van Hoesen,et al.  Alzheimer's disease: Glutamate depletion in the hippocampal perforant pathway zone , 1987, Annals of neurology.

[42]  W. Millard,et al.  Long-term neuropathological and neurochemical effects of nucleus basalis lesions in the rat. , 1987, Science.

[43]  M. Bennett,et al.  Differential expression of three glutamate receptor genes in developing rat brain: an in situ hybridization study. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[44]  M. Ball,et al.  NEUROFIBRILLARY TANGLES AND THE PATHOGENESIS OF DEMENTIA: A QUANTITATIVE STUDY , 1976 .

[45]  C. Cotman,et al.  N-methyl-d-aspartate receptor complex in the hippocampus of elderly, normal individuals and those with Alzheimer's disease , 1992, Neuroscience.

[46]  B. Sakmann,et al.  A family of AMPA-selective glutamate receptors. , 1990, Science.