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PMID: 18587408 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase.

Nature medicine ·Vol. 14 ·No. 7 ·2008-07-00 ·Pages 723-30

Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, St Laurent G, Kenny PJ, Wahlestedt C

Abstract

Recent efforts have revealed that numerous protein-coding messenger RNAs have natural antisense transcript partners, most of which seem to be noncoding RNAs. Here we identify a conserved noncoding antisense transcript for beta-secretase-1 (BACE1), a crucial enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript (BACE1-AS) regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-beta 1-42 (Abeta 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Abeta 1-42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice. These data show that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease-associated pathophysiology. In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of Abeta 1-42 in Alzheimer's disease.

MeSH Terms
Aged Aged, 80 and over Alzheimer Disease/enzymology,etiology,metabolism,physiopathology Amyloid Precursor Protein Secretases/genetics,metabolism Amyloid beta-Peptides/metabolism Animals Aspartic Acid Endopeptidases/genetics,metabolism Cell Line, Tumor Feedback, Physiological Gene Expression Regulation Humans Male Mice Mice, Transgenic Middle Aged Models, Genetic Neuroblastoma/pathology Peptide Fragments/metabolism Protein Processing, Post-Translational RNA, Messenger/metabolism RNA, Small Interfering/pharmacology RNA, Untranslated/analysis,metabolism Transcription, Genetic Transfection
Chemicals
Amyloid beta-Peptides Peptide Fragments RNA, Messenger RNA, Small Interfering RNA, Untranslated amyloid beta-protein (1-42) Amyloid Precursor Protein Secretases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Faghihi Mohammad Ali
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
Modarresi Farzaneh
Khalil Ahmad M
Wood Douglas E
Sahagan Barbara G
Morgan Todd E
Finch Caleb E
St Laurent Georges
Kenny Paul J
Wahlestedt Claes
References (49)
49 references, click to expand
  1. Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment.
    Arch Gen Psychiatry. 2007 Jun;64(6):718-26 PMID: 17548753
  2. Antisense transcription in the mammalian transcriptome.
    Science. 2005 Sep 2;309(5740):1564-6 PMID: 16141073
  3. Genetics of neurological disorders.
    Expert Rev Mol Diagn. 2004 May;4(3):317-32 PMID: 15137899
  4. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions.
    J Neurosci. 2005 Dec 14;25(50):11693-709 PMID: 16354928
  5. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease.
    Nature. 2008 Feb 7;451(7179):720-4 PMID: 18256671
  6. Alzheimer's disease: mRNA expression profiles of multiple patients show alterations of genes involved with calcium signaling.
    Neurobiol Dis. 2006 Mar;21(3):618-25 PMID: 16257224
  7. The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention.
    Biochem Soc Trans. 2005 Nov;33(Pt 5):1087-90 PMID: 16246051
  8. The beta-secretase, BACE: a prime drug target for Alzheimer's disease.
    J Mol Neurosci. 2001 Oct;17(2):157-70 PMID: 11816789
  9. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice.
    J Neurochem. 2004 Jun;89(5):1308-12 PMID: 15147524
  10. Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis.
    J Neurosci. 2007 Apr 4;27(14):3639-49 PMID: 17409228
  11. A century of Alzheimer's disease.
    Science. 2006 Nov 3;314(5800):777-81 PMID: 17082447
  12. Bace1 modulates myelination in the central and peripheral nervous system.
    Nat Neurosci. 2006 Dec;9(12):1520-5 PMID: 17099708
  13. Interfering with the brain: use of RNA interference for understanding the pathophysiology of psychiatric and neurological disorders.
    Pharmacol Ther. 2006 Mar;109(3):413-38 PMID: 16183135
  14. Control of peripheral nerve myelination by the beta-secretase BACE1.
    Science. 2006 Oct 27;314(5799):664-6 PMID: 16990514
  15. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss.
    Neuron. 2006 Dec 7;52(5):831-43 PMID: 17145504
  16. Inverse correlation between amyloid precursor protein and synaptic plasticity in transgenic mice.
    Neuroreport. 2007 Jul 2;18(10):1083-7 PMID: 17558301
  17. Temporal relations among amyloid beta-peptide-induced free-radical oxidative stress, neuronal toxicity, and neuronal defensive responses.
    J Mol Neurosci. 1998 Dec;11(3):183-97 PMID: 10344789
  18. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins.
    Nat Med. 2007 Nov;13(11):1359-62 PMID: 17934472
  19. Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model.
    Neurobiol Aging. 2003 May-Jun;24(3):397-413 PMID: 12600716
  20. Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer's disease.
    Biochem Soc Trans. 2005 Nov;33(Pt 5):1096-100 PMID: 16246054
  21. Control of APP processing and Abeta generation level by BACE1 enzymatic activity and transcription.
    FASEB J. 2006 Feb;20(2):285-92 PMID: 16449801
  22. Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase.
    J Neurosci. 2004 Jan 14;24(2):565-75 PMID: 14724257
  23. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice.
    J Biol Chem. 2007 Sep 7;282(36):26326-34 PMID: 17616527
  24. Oxidative stress potentiates BACE1 gene expression and Abeta generation.
    J Neural Transm (Vienna). 2005 Mar;112(3):455-69 PMID: 15614428
  25. Natural antisense and noncoding RNA transcripts as potential drug targets.
    Drug Discov Today. 2006 Jun;11(11-12):503-8 PMID: 16713901
  26. Transcriptional and translational regulation of BACE1 expression--implications for Alzheimer's disease.
    Prog Neurobiol. 2006 Jun;79(2):95-111 PMID: 16904810
  27. Gene expression profiles of metabolic enzyme transcripts in Alzheimer's disease.
    Brain Res. 2007 Jan 5;1127(1):127-35 PMID: 17109828
  28. Cerebral amyloidoses: molecular pathways and therapeutic challenges.
    Curr Med Chem. 2006;13(16):1903-13 PMID: 16842201
  29. CB1 receptor selective activation inhibits beta-amyloid-induced iNOS protein expression in C6 cells and subsequently blunts tau protein hyperphosphorylation in co-cultured neurons.
    Neurosci Lett. 2006 Sep 1;404(3):342-6 PMID: 16837132
  30. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
    Neuron. 2007 Jun 7;54(5):721-37 PMID: 17553422
  31. Noncoding RNAs: couplers of analog and digital information in nervous system function?
    Trends Neurosci. 2007 Dec;30(12):612-21 PMID: 17996312
  32. Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease.
    FASEB J. 2005 Feb;19(2):255-7 PMID: 15548589
  33. The increased activity of BACE1 correlates with oxidative stress in Alzheimer's disease.
    Neurobiol Aging. 2007 Jul;28(7):1009-14 PMID: 16769154
  34. Regulation of NMDA receptor trafficking by amyloid-beta.
    Nat Neurosci. 2005 Aug;8(8):1051-8 PMID: 16025111
  35. Mechanisms of beta-amyloid neurotoxicity: perspectives of pharmacotherapy.
    Rev Neurosci. 2000;11(4):329-82 PMID: 11065280
  36. Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression.
    Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18727-32 PMID: 17121991
  37. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease.
    Arch Neurol. 2002 Sep;59(9):1381-9 PMID: 12223024
  38. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.
    J Biol Chem. 2001 Jun 15;276(24):21562-70 PMID: 11279122
  39. Transvascular delivery of small interfering RNA to the central nervous system.
    Nature. 2007 Jul 5;448(7149):39-43 PMID: 17572664
  40. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients.
    Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3632-7 PMID: 14978286
  41. Involvement of beta-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity.
    Proc Natl Acad Sci U S A. 2007 May 8;104(19):8167-72 PMID: 17470798
  42. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease.
    Neuron. 2004 Jan 8;41(1):27-33 PMID: 14715132
  43. Inhibition of Abeta production and APP maturation by a specific PKA inhibitor.
    FEBS Lett. 2003 Jul 10;546(2-3):407-10 PMID: 12832078
  44. Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease.
    Ann Neurol. 2002 Jun;51(6):783-6 PMID: 12112088
  45. Phospholipases A2 mediate amyloid-beta peptide-induced mitochondrial dysfunction.
    J Neurosci. 2006 Oct 25;26(43):11111-9 PMID: 17065451
  46. Increased beta-Secretase activity in cerebrospinal fluid of Alzheimer's disease subjects.
    Ann Neurol. 2004 Jun;55(6):898-9 PMID: 15174031
  47. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.
    Neuron. 2005 Dec 22;48(6):913-22 PMID: 16364896
  48. Complex Loci in human and mouse genomes.
    PLoS Genet. 2006 Apr;2(4):e47 PMID: 16683030
  49. The various aggregation states of beta-amyloid 1-42 mediate different effects on oxidative stress, neurodegeneration, and BACE-1 expression.
    Free Radic Biol Med. 2006 Jul 15;41(2):202-12 PMID: 16814100
Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm1784
Published
2008-07-00
Epub
2008-00-29
Pages
723-30
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC2826895
Subset
IM
Grants
NIA NIH HHS · R21 AG029290 · United States
NIA NIH HHS · R21 AG029290-02 · United States
NIA NIH HHS · AG 029290 · United States
Corrections
CommentIn
PMID: 18607365
External Links
PubMed source DOI: 10.1038/nm1784 PMC Full Text View journal details
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