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PMID: 14769913 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 7 ·2004-02-17 ·Pages 2173-8

Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW

Abstract

The pathogenesis of incipient Alzheimer's disease (AD) has been resistant to analysis because of the complexity of AD and the overlap of its early-stage markers with normal aging. Gene microarrays provide new tools for addressing complexity because they allow overviews of the simultaneous activity of multiple cellular pathways. However, microarray data interpretation is often hindered by low statistical power, high false positives or false negatives, and by uncertain relevance to functional endpoints. Here, we analyzed hippocampal gene expression of nine control and 22 AD subjects of varying severity on 31 separate microarrays. We then tested the correlation of each gene's expression with MiniMental Status Examination (MMSE) and neurofibrillary tangle (NFT) scores across all 31 subjects regardless of diagnosis. These well powered tests revealed a major transcriptional response comprising thousands of genes significantly correlated with AD markers. Several hundred of these genes were also correlated with AD markers across only control and incipient AD subjects (MMSE > 20). Biological process categories associated with incipient AD-correlated genes were identified statistically (ease program) and revealed up-regulation of many transcription factor/signaling genes regulating proliferation and differentiation, including tumor suppressors, oligodendrocyte growth factors, and protein kinase A modulators. In addition, up-regulation of adhesion, apoptosis, lipid metabolism, and initial inflammation processes occurred, and down-regulation of protein folding/metabolism/transport and some energy metabolism and signaling pathways took place. These findings suggest a new model of AD pathogenesis in which a genomically orchestrated up-regulation of tumor suppressor-mediated differentiation and involution processes induces the spread of pathology along myelinated axons.

MeSH Terms
Algorithms Alzheimer Disease/genetics,pathology,physiopathology Calcium Signaling Cyclic AMP-Dependent Protein Kinases/metabolism Disease Progression Female Gene Expression Profiling Genes, Tumor Suppressor/physiology Hippocampus/metabolism,pathology,physiopathology Humans Male Oligonucleotide Array Sequence Analysis Transcription Factors/metabolism Transcription, Genetic/genetics
Chemicals
Transcription Factors Cyclic AMP-Dependent Protein Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Blalock Eric M
Department of Molecular and Biomedical Pharmacology, Spinal Cord and Brain Injury Research Center, and Sanders-Brown Research Center on Aging, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Geddes James W
Chen Kuey Chu
Porter Nada M
Markesbery William R
Landfield Philip W
References (76)
76 references, click to expand
  1. A gene expression profile of Alzheimer's disease.
    DNA Cell Biol. 2001 Nov;20(11):683-95 PMID: 11788046
  2. Cellular senescence as a tumor-suppressor mechanism.
    Trends Cell Biol. 2001 Nov;11(11):S27-31 PMID: 11684439
  3. Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous system.
    EMBO J. 2001 Jul 2;20(13):3402-13 PMID: 11432828
  4. Interpretation, design, and analysis of gene array expression experiments.
    J Gerontol A Biol Sci Med Sci. 2001 Feb;56(2):B52-7 PMID: 11213267
  5. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.
    J Neurosci. 2000 Jun 1;20(11):4050-8 PMID: 10818140
  6. Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer's disease.
    Ann N Y Acad Sci. 1994 Dec 15;747:77-91 PMID: 7847693
  7. Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1.
    J Neurosci. 2002 Jul 15;22(14):5992-6004 PMID: 12122061
  8. Adhesive defect in extracellular matrix tenascin-X-null fibroblasts: a possible mechanism of tumor invasion.
    Biol Pharm Bull. 2002 Nov;25(11):1472-5 PMID: 12419962
  9. "Preclinical" AD revisited: neuropathology of cognitively normal older adults.
    Neurology. 2000 Aug 8;55(3):370-6 PMID: 10932270
  10. Alzheimer's disease-related synapse loss in the cingulate cortex.
    J Alzheimers Dis. 2001 Oct;3(5):495-505 PMID: 12214036
  11. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.
    Science. 2002 Jul 19;297(5580):353-6 PMID: 12130773
  12. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation.
    Trends Cell Biol. 2002 Jun;12(6):258-66 PMID: 12074885
  13. The calcium rationale in aging and Alzheimer's disease. Evidence from an animal model of normal aging.
    Ann N Y Acad Sci. 1994 Dec 15;747:382-406 PMID: 7847686
  14. A cell-intrinsic timer that operates during oligodendrocyte development.
    Bioessays. 2000 Jan;22(1):64-71 PMID: 10649292
  15. Use of cDNA microarray in the search for molecular markers involved in the onset of Alzheimer's disease dementia.
    J Neurosci Res. 2001 Sep 15;65(6):471-6 PMID: 11550214
  16. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide.
    Nat Cell Biol. 2001 Oct;3(10):905-12 PMID: 11584272
  17. The Sp1 family of transcription factors is involved in p27(Kip1)-mediated activation of myelin basic protein gene expression.
    Mol Cell Biol. 2003 Jun;23(12):4035-45 PMID: 12773549
  18. The molecular genetics of Alzheimer's disease.
    Mol Neurobiol. 1994 Aug-Dec;9(1-3):15-22 PMID: 7888092
  19. Statin therapy for Alzheimer's disease: will it work?
    J Mol Neurosci. 2002 Aug-Oct;19(1-2):155-61 PMID: 12212773
  20. Mutant genes in familial Alzheimer's disease and transgenic models.
    Annu Rev Neurosci. 1998;21:479-505 PMID: 9530504
  21. Cdk5 is a key factor in tau aggregation and tangle formation in vivo.
    Neuron. 2003 May 22;38(4):555-65 PMID: 12765608
  22. Prostaglandins in the treatment of cancer.
    Anticancer Drugs. 1994 Apr;5(2):131-8 PMID: 8049495
  23. Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer's disease that eventually results in cell death.
    Ann N Y Acad Sci. 2000;920:249-55 PMID: 11193159
  24. The glial scar and central nervous system repair.
    Brain Res Bull. 1999 Aug;49(6):377-91 PMID: 10483914
  25. Learning and memory deficits in APP transgenic mouse models of amyloid deposition.
    Neurochem Res. 2003 Jul;28(7):1029-34 PMID: 12737527
  26. Inducible pRb2/p130 expression and growth-suppressive mechanisms: evidence of a pRb2/p130, p27Kip1, and cyclin E negative feedback regulatory loop.
    Cancer Res. 2000 May 15;60(10):2737-44 PMID: 10825149
  27. Evolution of neuronal changes in the course of Alzheimer's disease.
    J Neural Transm Suppl. 1998;53:127-40 PMID: 9700651
  28. Cell cycle proteins in Alzheimer's disease: plenty of wheels but no cycle.
    J Alzheimers Dis. 2002 Jun;4(3):249-54 PMID: 12226545
  29. The tumor suppressor interferon regulatory factor 1 interferes with SP1 activation to repress the human CDK2 promoter.
    J Biol Chem. 2003 Jul 18;278(29):26589-96 PMID: 12732645
  30. Mechanisms of astrocyte-directed neurite guidance.
    Cell Tissue Res. 1997 Nov;290(2):385-93 PMID: 9321702
  31. Overexpression of E2F1 in astrocytes leads to neoplastic transformation and changes in expression of retinoblastoma family members.
    J Neurosci Res. 1996 Oct 1;46(1):108-13 PMID: 8892111
  32. Diets enriched in foods with high antioxidant activity reverse age-induced decreases in cerebellar beta-adrenergic function and increases in proinflammatory cytokines.
    J Neurosci. 2002 Jul 15;22(14):6114-20 PMID: 12122072
  33. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex.
    Neuron. 2000 Oct;28(1):53-67 PMID: 11086983
  34. Treatment strategies for neurodegenerative diseases based on trophic factors and cell transplantation techniques.
    J Neural Transm Suppl. 1997;49:1-10 PMID: 9266409
  35. 'Unfolding' pathways in neurodegenerative disease.
    Trends Neurosci. 2003 Aug;26(8):407-10 PMID: 12900170
  36. Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase.
    FEBS Lett. 1998 Sep 25;436(1):28-34 PMID: 9771888
  37. Estrogens and estrogen-like non-feminizing compounds. Their role in the prevention and treatment of Alzheimer's disease.
    Ann N Y Acad Sci. 2000;924:93-8 PMID: 11193809
  38. Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease.
    Ann Neurol. 2002 Feb;51(2):182-9 PMID: 11835374
  39. Tau, where are we now?
    J Alzheimers Dis. 2002 Oct;4(5):375-98 PMID: 12446970
  40. Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats.
    Brain Res. 2000 Jun 2;866(1-2):211-7 PMID: 10825496
  41. Stereotyped pruning of long hippocampal axon branches triggered by retraction inducers of the semaphorin family.
    Cell. 2003 May 2;113(3):285-99 PMID: 12732138
  42. Response to "Interpretation, design, and analysis of gene array expression experiments".
    J Gerontol A Biol Sci Med Sci. 2001 Aug;56(8):B327-30 PMID: 11487590
  43. The neuropathological diagnosis of Alzheimer's disease: clinical-pathological studies.
    Neurobiol Aging. 1997 Jul-Aug;18(4 Suppl):S27-32 PMID: 9330982
  44. Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease.
    Arch Neurol. 1999 Jul;56(7):857-62 PMID: 10404988
  45. Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease.
    J Neuropathol Exp Neurol. 1997 Aug;56(8):933-44 PMID: 9258263
  46. Inflammation and Alzheimer's disease pathogenesis.
    Neurobiol Aging. 1996 Sep-Oct;17(5):681-6 PMID: 8892340
  47. Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
    Trends Neurosci. 2001 Apr;24(4):219-24 PMID: 11250006
  48. Comparison of neuropathologic criteria for the diagnosis of Alzheimer's disease.
    Neurobiol Aging. 1997 Jul-Aug;18(4 Suppl):S99-105 PMID: 9330997
  49. 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.
    J Neurosci Res. 2002 Nov 1;70(3):462-73 PMID: 12391607
  50. Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders.
    Trends Neurosci. 2000 May;23(5):222-9 PMID: 10782128
  51. Clinical-neuropathological correlations in Alzheimer's disease and related dementias.
    Arch Neurol. 1994 Sep;51(9):888-95 PMID: 8080388
  52. C1q arrests the cell cycle progression of fibroblasts in G(1) phase: role of the cAMP/PKA-I pathway.
    Cell Signal. 2001 Feb;13(2):119-23 PMID: 11257456
  53. Controlling the false discovery rate in behavior genetics research.
    Behav Brain Res. 2001 Nov 1;125(1-2):279-84 PMID: 11682119
  54. Mechanisms of neuronal death in brain aging and Alzheimer's disease: role of endocrine-mediated calcium dyshomeostasis.
    J Neurobiol. 1992 Nov;23(9):1247-60 PMID: 1469387
  55. Cells differentiating into neuroectoderm undergo apoptosis in the absence of functional retinoblastoma family proteins.
    J Cell Biol. 1995 May;129(3):779-88 PMID: 7730411
  56. EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression.
    Neuron. 2001 May;30(2):355-68 PMID: 11394999
  57. Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons.
    Ann Neurol. 2000 Jul;48(1):77-87 PMID: 10894219
  58. Microarrays: biotechnology's discovery platform for functional genomics.
    Trends Biotechnol. 1998 Jul;16(7):301-6 PMID: 9675914
  59. Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment.
    J Neurosci. 2003 May 1;23(9):3807-19 PMID: 12736351
  60. The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar.
    J Neurosci. 1999 Dec 15;19(24):10778-88 PMID: 10594061
  61. pRb2/p130 gene overexpression induces astrocyte differentiation.
    Mol Cell Neurosci. 2001 Mar;17(3):415-25 PMID: 11273639
  62. Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer's disease.
    Neurobiol Dis. 2003 Mar;12(2):97-109 PMID: 12667465
  63. Synapse formation between central neurons requires postsynaptic expression of the MEN1 tumor suppressor gene.
    J Neurosci. 2001 Aug 15;21(16):RC161 PMID: 11473132
  64. New frontiers in Alzheimer's disease genetics.
    Neuron. 2001 Oct 25;32(2):181-4 PMID: 11683989
  65. Interactions of oxidative stress with cellular calcium dynamics and glucose metabolism in Alzheimer's disease.
    Free Radic Biol Med. 2002 Jun 1;32(11):1061-70 PMID: 12031890
  66. Myelin and collapsin-1 induce motor neuron growth cone collapse through different pathways: inhibition of collapse by opposing mutants of rac1.
    J Neurosci. 1999 Mar 15;19(6):1965-75 PMID: 10066250
  67. Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice.
    J Neurosci. 2003 Jun 15;23(12):5219-26 PMID: 12832546
  68. Protein oxidation in the brain in Alzheimer's disease.
    Neuroscience. 2001;103(2):373-83 PMID: 11246152
  69. The neuronal endosomal-lysosomal system in Alzheimer's disease.
    J Alzheimers Dis. 2001 Feb;3(1):97-107 PMID: 12214078
  70. DNA arrays and neurobiology--what's new and what's next?
    Curr Opin Neurobiol. 2002 Oct;12(5):554-61 PMID: 12367635
  71. Fibroblast growth factor receptor 3 signaling regulates the onset of oligodendrocyte terminal differentiation.
    J Neurosci. 2003 Feb 1;23(3):883-94 PMID: 12574417
  72. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
    Nat Genet. 2000 May;25(1):25-9 PMID: 10802651
  73. Calcium dysregulation in neuronal aging and Alzheimer's disease: history and new directions.
    Cell Calcium. 1998 Nov-Dec;24(5-6):417-33 PMID: 10091010
  74. Correlates of p53- and Fas (CD95)-mediated apoptosis in Alzheimer's disease.
    J Neurol Sci. 1997 Nov 6;152(1):73-83 PMID: 9395128
  75. Synaptic and neuritic alterations during the progression of Alzheimer's disease.
    Neurosci Lett. 1994 Jun 6;174(1):67-72 PMID: 7970158
  76. Interleukin-1, neuroinflammation, and Alzheimer's disease.
    Neurobiol Aging. 2001 Nov-Dec;22(6):903-8 PMID: 11754997
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0308512100
Published
2004-02-17
Epub
2004-00-09
Pages
2173-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC357071
Subset
IM
Grants
NIA NIH HHS · P01 AG010836 · United States
NIA NIH HHS · P50 AG005144 · United States
NIA NIH HHS · AG05144 · United States
NIA NIH HHS · AG10836 · United States
External Links
PubMed source DOI: 10.1073/pnas.0308512100 PMC Full Text View journal details
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