Interleukin-1β and Glutamate Activate the NF-κB/Rel Binding Site from the Regulatory Region of the Amyloid Precursor Protein Gene in Primary Neuronal Cultures*

We originally reported that members of the family of transcription factors NF-κB/Rel can specifically recognize two identical sequences, referred to as APPκB sites, which are present in the 5′-regulatory region of the APP gene. Here we show that the APPκB sites interact specifically with a complex which contains one of the subunits of the family, defined as p50 protein, and that they act as positive modulators of gene transcription in cells of neural origin. Additionally, the nuclear complex specifically binding to the APPκB sites is constitutively expressed in primary neurons from rat cerebellum and it is up-regulated in response to both the inflammatory cytokine interleukin-1β (IL-1β) and the excitatory amino acid glutamate. Since IL-1, whose levels are known to be induced in brain of individuals affected by Alzheimer's disease, and glutamate, are stimuli which have been regarded as major actors on the stage of neurodegenerative processes, we believe our evidence as potentially relevant for understanding the neuropathology associated with Alzheimer's disease.

[1]  M. Memo,et al.  Identification and Characterization of a κB/Rel Binding Site in the Regulatory Region of the Amyloid Precursor Protein Gene (*) , 1995, The Journal of Biological Chemistry.

[2]  R. Tanzi,et al.  The upstream stimulatory factor functionally interacts with the Alzheimer amyloid beta-protein precursor gene. , 1995, Human molecular genetics.

[3]  D. Goldgaber,et al.  USF binds to the APBα sequence in the promoter of the amyloid β-protein precursor gene , 1995 .

[4]  J. Zweier,et al.  Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide , 1995, Nature Medicine.

[5]  M. Memo,et al.  Opposing regulation of amyloid precursor protein by ionotropic and metabotropic glutamate receptors. , 1995, Neuroreport.

[6]  E. Wijsman,et al.  Beta APP mRNA transcription is increased in cultured fibroblasts from the familial Alzheimer's disease-1 family. , 1995, Brain research. Molecular brain research.

[7]  J. Trejo,et al.  A direct role for protein kinase C and the transcription factor Jun/AP-1 in the regulation of the Alzheimer's beta-amyloid precursor protein gene. , 1994, The Journal of biological chemistry.

[8]  W. Quitschke.  Two nuclear factor binding domains activate expression from the human amyloid beta-protein precursor promoter. , 1994, The Journal of biological chemistry.

[9]  H. Neumann,et al.  Constitutive NF-kappa B activity in neurons , 1994, Molecular and cellular biology.

[10]  S. Lipton,et al.  Excitatory amino acids as a final common pathway for neurologic disorders. , 1994, The New England journal of medicine.

[11]  M. Korner,et al.  NF‐kappa B activates the HIV promoter in neurons. , 1993, The EMBO journal.

[12]  P. Baeuerle,et al.  Brain synapses contain inducible forms of the transcription factor NF-κB , 1993, Mechanisms of Development.

[13]  David Baltimore,et al.  Regulation of the NF-?B/rel transcription factor and I?B inhibitor system , 1993 .

[14]  G. Forloni,et al.  Expression of amyloid precursor protein mRNAs in endothelial, neuronal and glial cells: modulation by interleukin-1. , 1992, Brain research. Molecular brain research.

[15]  K. Yoshikawa,et al.  Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor , 1992, Nature.

[16]  D. Goldgaber,et al.  The amyloid beta-protein precursor promoter. A region essential for transcriptional activity contains a nuclear factor binding domain. , 1992, The Journal of biological chemistry.

[17]  M. Grilli,et al.  NF-kappa B subunit regulation in nontransformed CD4+ T lymphocytes. , 1992, Science.

[18]  Colin L. Masters,et al.  The expression of the amyloid precursor protein (APP) is regulated by two GC-elements in the promoter , 1992, Nucleic Acids Res..

[19]  D. Graham,et al.  βA4 amyloid protein deposition in brain after head trauma , 1991, The Lancet.

[20]  S. Hirai,et al.  Expression of APP in the early stage of brain damage , 1991, Brain Research.

[21]  J. Hardy,et al.  Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene , 1991, Nature.

[22]  N. Andrews,et al.  A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. , 1991, Nucleic acids research.

[23]  R. Tanzi,et al.  Induction of amyloid precursor protein mRNA after heat shock in cultured human lymphoblastoid cells , 1991, Neuroscience Letters.

[24]  R. Tanzi,et al.  Selective induction of Kunitz-type protease inhibitor domain-containing amyloid precursor protein mRNA after persistent focal ischemia in rat cerebral cortex , 1991, Neuroscience Letters.

[25]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[26]  N. Robakis,et al.  The promoter activity of the gene encoding Alzheimer beta-amyloid precursor protein (APP) is regulated by two blocks of upstream sequences. , 1991, Brain research. Molecular brain research.

[27]  M. Korner,et al.  Nuclear factor kappa B activates proenkephalin transcription in T lymphocytes , 1991, Molecular and cellular biology.

[28]  C. Finch,et al.  Relation of neuronal APP-751/APP-695 mRNA ratio and neuritic plaque density in Alzheimer's disease. , 1990, Science.

[29]  H. W. Harris,et al.  Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[30]  W. Griffin,et al.  Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Robert B. Nelson,et al.  Expression of β-amyloid precursor protein in reactive astrocytes following neuronal damage , 1989, Neuron.

[32]  N. Robakis,et al.  Characterization of the 5'-end region and the first two exons of the beta-protein precursor gene. , 1989, Biochemical and biophysical research communications.

[33]  R. Neve,et al.  Expression of the Alzheimer amyloid precursor gene transcripts in the human brain , 1988, Neuron.

[34]  K. Beyreuther,et al.  The promoter of Alzheimer's disease amyloid A4 precursor gene. , 1988, Progress in clinical and biological research.

[35]  J. Morrison,et al.  Differential regulation of amyloid-beta-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Younkin,et al.  In situ hybridization of nucleus basalis neurons shows increased beta-amyloid mRNA in Alzheimer disease. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[37]  B. Luckow,et al.  CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements , 1987, Nucleic Acids Res..

[38]  V. Gallo,et al.  Selective release of glutamate from cerebellar granule cells differentiating in culture. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[39]  I. Pastan,et al.  The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Selkoe,et al.  Normal and abnormal biology of the beta-amyloid precursor protein. , 1994, Annual review of neuroscience.

[41]  M. Grilli,et al.  NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. , 1993, International review of cytology.

[42]  J. Palacios,et al.  Increased levels of the Kunitz protease inhibitor-containing beta APP mRNAs in rat brain following neurotoxic damage. , 1993, Brain research. Molecular brain research.

[43]  N. Rothwell,et al.  Functions and mechanisms of interleukin 1 in the brain. , 1991, Trends in pharmacological sciences.

[44]  M. Edbrooke,et al.  Identification of cis-acting sequences responsible for phorbol ester induction of human serum amyloid A gene expression via a nuclear factor kappaB-like transcription factor , 1989, Molecular and cellular biology.