title: An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's disease is the most frequent age-related dementia, and is currently without treatment. To identify possible targets for early therapeutic intervention we focused on glutamate excitotoxicity, a major early pathogenic factor, and the effects of candesartan, an angiotensin receptor blocker of neuroprotective efficacy in cell cultures and rodent models of Alzheimer's disease. The overall goal of the study was to determine whether gene analysis of drug effects in a primary neuronal culture correlate with alterations in gene expression in Alzheimer's disease, thus providing further preclinical evidence of beneficial therapeutic effects.
  
  
  METHODS
  Primary neuronal cultures were treated with candesartan at neuroprotective concentrations followed by excitotoxic glutamate amounts. We performed genome-wide expression profile analysis and data evaluation by ingenuity pathway analysis and gene set enrichment analysis, compared with alterations in gene expression from two independent published datasets identified by microarray analysis of postmortem hippocampus from Alzheimer's disease patients. Preferential expression in cerebrovascular endothelial cells or neurons was analyzed by comparison to published gene expression in these cells isolated from human cortex by laser capture microdissection.
  
  
  RESULTS
  Candesartan prevented glutamate upregulation or downregulation of several hundred genes in our cultures. Ingenuity pathway analysis and gene set enrichment analysis revealed that inflammation, cardiovascular disease and diabetes signal transduction pathways and amyloid β metabolism were major components of the neuronal response to glutamate excitotoxicity. Further analysis showed associations of glutamate-induced changes in the expression of several hundred genes, normalized by candesartan, with similar alterations observed in hippocampus from Alzheimer's disease patients. Gene analysis of neurons and cerebrovascular endothelial cells obtained by laser capture microdissection revealed that genes up- and downregulated by glutamate were preferentially expressed in endothelial cells and neurons, respectively.
  
  
  CONCLUSIONS
  Our data may be interpreted as evidence of direct candesartan neuroprotection beyond its effects on blood pressure, revealing common and novel disease mechanisms that may underlie the in vitro gene alterations reported here and glutamate-induced cell injury in Alzheimer's disease. Our observations provide novel evidence for candesartan neuroprotection through early molecular mechanisms of injury in Alzheimer's disease, supporting testing this compound in controlled clinical studies in the early stages of the illness.
authors.affiliation: Comparative genomics and Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. abdel@nhgri.nih.gov.
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.affiliation: Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA. roman.hafko@gmail.com.
authors.forename: Roman
authors.initials: R
authors.lastname: Hafko
authors.affiliation: Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA. jms522@georgetown.edu.|Department of Pharmacology and Physiology, Georgetown University Medical Center, SE402 Med/Dent, 3900 Reservoir Road, Washington, DC, 20057, USA. jms522@georgetown.edu.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Saavedra
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D016208:Databases, Factual; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D013777:Tetrazoles; D018698:Glutamic Acid; C081643:candesartan
references.citation: Am J Pathol. 2000 Jan;156(1):139-50
references.pmid: 10623661
references.citation: Stroke. 2000 Oct;31(10):2478-86
references.pmid: 11022082
references.citation: J Hum Hypertens. 2002 Aug;16 Suppl 3:S71-5
references.pmid: 12140732
references.citation: Stroke. 2002 Sep;33(9):2297-303
references.pmid: 12215602
references.citation: Biochem Biophys Res Commun. 2003 Jan 31;301(1):231-5
references.pmid: 12535668
references.citation: Nat Genet. 2003 Jul;34(3):267-73
references.pmid: 12808457
references.citation: Cerebellum. 2002 Jan-Mar;1(1):41-55
references.pmid: 12879973
references.citation: J Clin Endocrinol Metab. 2003 Sep;88(9):4496-501
references.pmid: 12970329
references.citation: Neurochem Int. 2004 Jan;44(2):107-18
references.pmid: 12971913
references.citation: Eur J Clin Pharmacol. 2004 Feb;59(12):863-8
references.pmid: 14747881
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2173-8
references.pmid: 14769913
references.citation: Exp Cell Res. 2004 Apr 15;295(1):245-57
references.pmid: 15051507
references.citation: J Immunol. 2004 May 15;172(10):6362-72
references.pmid: 15128827
references.citation: Stroke. 2004 Jul;35(7):1726-31
references.pmid: 15143297
references.citation: J Lipid Res. 2005 May;46(5):949-68
references.pmid: 15716586
references.citation: J Cereb Blood Flow Metab. 2005 Jul;25(7):878-86
references.pmid: 15729290
references.citation: J Neurochem. 2005 Apr;93(1):145-55
references.pmid: 15773914
references.citation: Endocr Rev. 1992 May;13(2):329-80
references.pmid: 1618166
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Clin Sci (Lond). 2007 Jun;112(7):375-84
references.pmid: 17324119
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1358-75
references.pmid: 17481747
references.citation: J Clin Invest. 2007 Nov;117(11):3393-402
references.pmid: 17965777
references.citation: Eur J Neurosci. 2008 Jan;27(2):343-51
references.pmid: 18190523
references.citation: J Mol Med (Berl). 2008 Jun;86(6):715-22
references.pmid: 18385968
references.citation: Curr Alzheimer Res. 2008 Apr;5(2):187-201
references.pmid: 18393804
references.citation: PLoS One. 2008;3(12):e3964
references.pmid: 19088852
references.citation: J Cereb Blood Flow Metab. 2009 Mar;29(3):640-7
references.pmid: 19127280
references.citation: J Alzheimers Dis. 2009;16(1):49-57
references.pmid: 19158421
references.citation: J Vis Exp. 2009 Jan 16;(23):null
references.pmid: 19229177
references.citation: Hypertension. 2009 Oct;54(4):782-7
references.pmid: 19635982
references.citation: J Hypertens. 2009 Dec;27(12):2365-76
references.pmid: 19730394
references.citation: Exp Gerontol. 2010 Jan;45(1):75-9
references.pmid: 19782124
references.citation: BMC Geriatr. 2009 Nov 18;9:48
references.pmid: 19922631
references.citation: Lancet. 2009 Nov 28;374(9704):1840-8
references.pmid: 19922995
references.citation: J Biol Chem. 2010 Jan 15;285(3):1577-81
references.pmid: 19926786
references.citation: BMJ. 2010 Jan 12;340:b5465
references.pmid: 20068258
references.citation: Behav Brain Res. 2010 May 1;209(1):165-73
references.pmid: 20122965
references.citation: Curr Clin Pharmacol. 2010 May;5(2):89-95
references.pmid: 20156154
references.citation: J Hypertens. 2010 Mar;28(3):429
references.pmid: 20160578
references.citation: Methods Mol Biol. 2010;633:233-9
references.pmid: 20204632
references.citation: Pflugers Arch. 2010 Jul;460(2):525-42
references.pmid: 20229265
references.citation: Rejuvenation Res. 2010 Apr-Jun;13(2-3):195-201
references.pmid: 20370487
references.citation: Eur J Neurosci. 2010 Mar;31(5):852-63
references.pmid: 20374285
references.citation: Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5336-42
references.pmid: 20484595
references.citation: Genome Biol Evol. 2010 Jul 12;2:284-92
references.pmid: 20624733
references.citation: J Leukoc Biol. 2010 Oct;88(4):687-97
references.pmid: 20628063
references.citation: Br J Pharmacol. 2010 Sep;161(1):33-50
references.pmid: 20718738
references.citation: J Immunol. 2010 Nov 15;185(10):6317-28
references.pmid: 20962261
references.citation: Psychoneuroendocrinology. 2011 Jan;36(1):1-18
references.pmid: 21035950
references.citation: Neuropsychopharmacology. 2011 Mar;36(4):857-70
references.pmid: 21150913
references.citation: PLoS One. 2011 Jan 28;6(1):e16037
references.pmid: 21297982
references.citation: J Biol Chem. 2011 May 6;286(18):16374-85
references.pmid: 21454555
references.citation: J Alzheimers Dis. 2011;26(4):699-708
references.pmid: 21709373
references.citation: Int J Hypertens. 2012;2012:320648
references.pmid: 22121477
references.citation: J Hypertens. 2012 Jan;30(1):87-96
references.pmid: 22124178
references.citation: J Neuroinflammation. 2011 Dec 15;8:175
references.pmid: 22171672
references.citation: PLoS One. 2012;7(1):e28033
references.pmid: 22276093
references.citation: J Alzheimers Dis. 2012;29(4):853-61
references.pmid: 22330820
references.citation: Nat Neurosci. 2012 Jun;15(6):827-35
references.pmid: 22610069
references.citation: J Neuroinflammation. 2012 May 29;9:102
references.pmid: 22642771
references.citation: Br J Pharmacol. 2012 Sep;167(2):324-52
references.pmid: 22646481
references.citation: Clin Sci (Lond). 2012 Nov;123(10):567-90
references.pmid: 22827472
references.citation: Neuropsychopharmacology. 2012 Dec;37(13):2817-29
references.pmid: 22892395
references.citation: Basic Clin Pharmacol Toxicol. 2013 Mar;112(3):145-55
references.pmid: 22913737
references.citation: Neurosci Lett. 2012 Sep 27;526(2):112-7
references.pmid: 22925659
references.citation: Behav Brain Res. 2012 Dec 1;235(2):200-9
references.pmid: 22963993
references.citation: FEBS Lett. 2012 Oct 19;586(20):3737-45
references.pmid: 22982863
references.citation: Clin Exp Pharmacol Physiol. 2012 Oct;39(10):852-7
references.pmid: 23013130
references.citation: Biochem Pharmacol. 2013 Feb 1;85(3):289-305
references.pmid: 23178653
references.citation: Biol Pharm Bull. 2012;35(12):2141-7
references.pmid: 23207766
references.citation: FEBS Lett. 2013 Jan 16;587(2):254-8
references.pmid: 23238080
references.citation: Neurosci Res. 2013 Feb;75(2):94-102
references.pmid: 23257508
references.citation: Pharmacol Res. 2013 Apr;70(1):116-25
references.pmid: 23376356
references.citation: Pharmacol Rev. 2013 Mar 13;65(2):809-48
references.pmid: 23487168
references.citation: Alzheimers Dement. 2013 Mar;9(2):208-45
references.pmid: 23507120
references.citation: CNS Neurosci Ther. 2013 Aug;19(8):549-55
references.pmid: 23593992
references.citation: Cereb Cortex. 2014 Sep;24(9):2476-88
references.pmid: 23595620
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):E2518-27
references.pmid: 23776240
references.citation: Expert Opin Investig Drugs. 2013 Oct;22(10):1229-42
references.pmid: 23800077
references.citation: Neuropsychopharmacology. 2014 Jan;39(2):401-14
references.pmid: 23954849
references.citation: Int J Mol Sci. 2013 Aug 16;14(8):16917-42
references.pmid: 23959119
references.citation: Oncogene. 2014 Jul 10;33(28):3648-59
references.pmid: 23975427
references.citation: J Clin Invest. 2013 Oct;123(10):4158-69
references.pmid: 23999428
references.citation: J Cereb Blood Flow Metab. 2013 Nov;33(11):1696-706
references.pmid: 24022624
references.citation: Am J Cardiovasc Dis. 2013 Nov 01;3(4):197-226
references.pmid: 24224133
references.citation: Curr Alzheimer Res. 2014 Jan;11(1):4-10
references.pmid: 24251391
references.citation: Curr Alzheimer Res. 2014 Jan;11(1):18-26
references.pmid: 24251393
references.citation: Neuron. 2013 Nov 20;80(4):844-66
references.pmid: 24267647
references.citation: Neuropharmacology. 2014 Apr;79:249-61
references.pmid: 24316465
references.citation: Mol Cell Endocrinol. 2014 May 25;389(1-2):40-7
references.pmid: 24424441
references.citation: J Alzheimers Dis. 2014;41(2):331-43
references.pmid: 24614908
references.citation: Nat Rev Neurol. 2014 Apr;10(4):217-24
references.pmid: 24638131
references.citation: Front Aging Neurosci. 2014 Mar 13;6:32
references.pmid: 24659966
references.citation: Biochim Biophys Acta. 2014 Aug;1837(8):1338-49
references.pmid: 24709060
references.citation: Curr Neurovasc Res. 2014 May;11(2):168-76
references.pmid: 24712646
references.citation: Front Aging Neurosci. 2014 Mar 24;6:24
references.pmid: 24715862
references.citation: J Mol Neurosci. 2014;54(2):271-81
references.pmid: 24729128
references.citation: PLoS One. 2014 Apr 22;9(4):e95413
references.pmid: 24755620
references.citation: Neurobiol Aging. 2015 Jan;36(1):111-22
references.pmid: 25085784
references.citation: Front Aging Neurosci. 2014 Jul 29;6:171
references.pmid: 25120476
references.citation: Neuroscience. 2015 Aug 27;302:103-11
references.pmid: 25286385
references.citation: Exp Gerontol. 2014 Dec;60:87-91
references.pmid: 25304332
references.citation: Front Aging Neurosci. 2014 Sep 11;6:238
references.pmid: 25309424
references.citation: Am J Hypertens. 2015 Mar;28(3):289-99
references.pmid: 25362113
references.citation: J Neurosci Res. 2015 Mar;93(3):475-86
references.pmid: 25400096
references.citation: Ann Neurol. 2015 Apr;77(4):637-54
references.pmid: 25611954
references.citation: CNS Drugs. 2015 Feb;29(2):113-30
references.pmid: 25700645
references.citation: Biochim Biophys Acta. 2015 Jul;1852(7):1428-41
references.pmid: 25857617
references.citation: Horm Behav. 2015 Aug;74:28-36
references.pmid: 25993604
references.citation: Hypertension. 1995 Jan;25(1):14-21
references.pmid: 7843746
references.citation: Science. 1993 Oct 29;262(5134):689-95
references.pmid: 7901908
references.citation: J Biol Chem. 1994 Oct 14;269(41):25277-82
references.pmid: 7929219
references.citation: Pharmacol Rev. 1993 Jun;45(2):205-51
references.pmid: 8372104
references.citation: Brain Res. 1995 Dec 12;703(1-2):63-71
references.pmid: 8719616