Supplemental Table 2 Literature verification of the gene sets obtained from the
cent-stat method in AD
GO term
GO term
ACTIN BINDING[1]
NEGATIVE REGULATION OF PROGRAMMED
CELL DEATH[2]
ACTIN CYTOSKELETON ORGANIZATION AND NEGATIVE
REGULATION
BIOGENESIS[3]
METABOLIC PROCESS
ACTIN FILAMENT BASED PROCESS
NEGATIVE
OF
REGULATION
RNA
OF
TRANSCRIPTION[4]
ACTIN FILAMENT BINDING[1]
NEGATIVE REGULATION OF TRANSCRIPTION
DNA DEPENDENT
ACTIN FILAMENT BUNDLE FORMATION
NERVOUS SYSTEM DEVELOPMENT[5]
ACTIN FILAMENT ORGANIZATION[6]
NEUROPEPTIDE HORMONE ACTIVITY[4]
ACTIVATION OF NF KAPPAB TRANSCRIPTION NUCLEAR CHROMOSOME PART
FACTOR[7]
AEROBIC RESPIRATION[8]
NUCLEAR IMPORT[9]
ANTI APOPTOSIS[10]
NUCLEAR LUMEN
APOPTOSIS GO
NUCLEAR TRANSPORT[11]
CELLULAR LOCALIZATION[12]
NUCLEOBASE
NUCLEOSIDE
NUCLEOTIDE KINASE ACTIVITY[13]
CELLULAR RESPIRATION[14, 15]
CENTRAL
NERVOUS
NUCLEOCYTOPLASMIC TRANSPORT[16]
SYSTEM NUCLEOSIDE
TRIPHOSPHATASE
DEVELOPMENT[17]
ACTIVITY[18]
CHROMATIN MODIFICATION[19]
ORGANELLE ENVELOPE[20]
CHROMOSOME
ORGANIZATION
AND ORGANELLE INNER MEMBRANE[4]
BIOGENESIS[21]
CLATHRIN COATED VESICLE[22]
ORGANELLE LUMEN
COATED VESICLE[23]
ORGANELLE MEMBRANE[24]
COFACTOR CATABOLIC PROCESS[25]
ORGANELLE
ORGANIZATION
AND
BIOGENESIS
COVALENT CHROMATIN MODIFICATION
PEPTIDE METABOLIC PROCESS
CYTOPLASMIC MEMBRANE BOUND VESICLE
PHOSPHOTRANSFERASE
ACTIVITY
PHOSPHATE GROUP AS ACCEPTOR
CYTOPLASMIC VESICLE[26]
POSITIVE REGULATION OF BINDING
CYTOSKELETAL PROTEIN BINDING
POSITIVE REGULATION OF DNA BINDING
CYTOSKELETON[27]
POSITIVE REGULATION OF I KAPPAB KINASE
NF KAPPAB CASCADE
CYTOSKELETON
ORGANIZATION
AND POSITIVE
BIOGENESIS[28]
REGULATION
OF
SIGNAL
TRANSDUCTION
ENERGY DERIVATION BY OXIDATION OF POSITIVE REGULATION OF TRANSCRIPTION
ORGANIC COMPOUNDS[29, 30]
FACTOR ACTIVITY
ENVELOPE[31]
POST
TRANSLATIONAL
PROTEIN
MODIFICATION[32]
ESTABLISHMENT AND OR MAINTENANCE OF PROGRAMMED CELL DEATH[33]
CHROMATIN ARCHITECTURE
ESTABLISHMENT
OF
CELLULAR PROTEIN IMPORT
LOCALIZATION[34]
ESTABLISHMENT
OF
PROTEIN PROTEIN KINASE CASCADE[36]
LOCALIZATION[35]
GTP BINDING[37]
PROTEIN LOCALIZATION[35]
GTPASE ACTIVITY[38]
PROTEIN
SERINE
THREONINE
KINASE
ACTIVITY[39]
HISTONE MODIFICATION[40]
HYDROLASE ACTIVITY
PROTEIN TARGETING
ACTING ON ACID PROTON TRANSPORTING TWO SECTOR
ANHYDRIDES
ATPASE COMPLEX[41]
I KAPPAB KINASE NF KAPPAB CASCADE[42]
PYROPHOSPHATASE ACTIVITY[43]
IDENTICAL PROTEIN BINDING[44]
REGULATION OF APOPTOSIS[45]
INTRACELLULAR TRANSPORT[46]
REGULATION OF BINDING[24]
KINASE ACTIVITY[47]
REGULATION
OF
DEVELOPMENTAL
PROCESS
MACROMOLECULE LOCALIZATION
REGULATIO N OF DNA BINDING[48]
MAP KINASE KINASE KINASE ACTIVITY[49]
REGULATION
OF
ENDOTHELIAL
CELL
PROLIFERATION
MEMBRANE BOUND VESICLE
REGULATION OF I KAPPAB KINASE NF
KAPPAB CASCADE
MEMBRANE ENCLOSED LUMEN
REGULATION
OF
MOLECULAR
FUNCTION[50]
MEMBRANE
ORGANIZATION
AND REGULATION
OF
PROGRAMMED
CELL
BIOGENESIS[51]
DEATH
MITOCHONDRIAL ENVELOPE
REGULATION OF RNA METABOLIC PROCESS
MITOCHONDRIAL INNER MEMBRANE[52]
REGULATION OF TRANSCRIPTION
DNA
DEPENDENT
MITOCHONDRIAL MEMBRANE[53]
REGULATION OF TRANSCRIPTION FACTOR
ACTIVITY[54]
MITOCHONDRIAL
MEMBRANE REGULATION OF TRANSCRIPTION FROM
ORGANIZATION AND BIOGENESIS
RNA POLYMERASE II PROMOTER
MITOCHONDRIAL MEMBRANE PART[53]
RIBONUCLEOPROTEIN COMPLEX[55]
MITOCHONDRIAL OUTER MEMBRANE[56]
RNA PROCESSING[57]
MITOCHONDRIAL PART[58]
SMALL CONJUGATING PROTEIN BINDING
MITOCHONDRIAL TRANSPORT[59]
SYNAPTIC VESICLE[60]
MITOCHONDRION[61]
TRANSCRIPTION FACTOR BINDING
MITOCHONDRION
BIOGENESIS
ORGANIZATION
AND TRANSCRIPTION FROM RNA POLYMERASE II
PROMOTER
NEGATIVE REGULATION OF APOPTOSIS
NEGATIVE
REGULATION
COMPONENT
OF
TRANSCRIPTION REPRESSOR ACTIVITY[62]
CELLULAR TRANSFERASE ACTIVITY
ORGANIZATION
TRANSFERRING
AND PHOSPHORUS CONTAINING GROUPS
BIOGENESIS
NEGATIVE
REGULATION
OF
CELLULAR TRANSPORT VESICLE[63]
METABOLIC PROCESS
NEGATIVE REGULATION OF DEVELOPMENTAL TRICARBOXYLIC ACID CYCLE INTERMEDIATE
PROCESS
NEGATIVE
METABOLIC PROCESS
REGULATION
OF
METABOLIC TRNA PROCESSING
PROCESS
NEGATIVE REGULATION OF NUCLEOBASE UBIQUITIN BINDING[64, 65]
NUCLEOSIDE
NUCLEOTIDE AND NUCLEIC
ACID METABOLIC PROCESS
Reference:
1.
Harigaya Y, Shoji M, Shirao T, Hirai S: Disappearance of actin-binding protein, drebrin, from
hippocampal synapses in Alzheimer's disease. J Neurosci Res 1996, 43:87-92.
2.
Stadelmann C, Deckwerth TL, Srinivasan A, Bancher C, Bruck W, Jellinger K, Lassmann H:
Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar
degeneration in Alzheimer's disease. Evidence for apoptotic cell death. Am J Pathol 1999,
155:1459-1466.
3.
Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL, Hyman BT, Feany MB: Abnormal
bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo.
Nat Cell Biol 2007, 9:139-148.
4.
Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ: 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, 70:462-473.
5.
Martin LJ: Neuronal cell death in nervous system development, disease, and injury (Review).
Int J Mol Med 2001, 7:455-478.
6.
Heredia L, Helguera P, de Olmos S, Kedikian G, Sola Vigo F, LaFerla F, Staufenbiel M, de Olmos
J, Busciglio J, Caceres A, Lorenzo A: Phosphorylation of actin-depolymerizing factor/cofilin
by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of
neuronal dystrophy in Alzheimer's disease. J Neurosci 2006, 26:6533-6542.
7.
Terai K, Matsuo A, McGeer PL: Enhancement of immunoreactivity for NF-kappa B in the
hippocampal formation and cerebral cortex of Alzheimer's disease. Brain Res 1996,
735:159-168.
8.
Datta K, Sinha S, Chattopadhyay P: Reactive oxygen species in health and disease. Natl Med J
India 2000, 13:304-310.
9.
Engidawork E, Gulesserian T, Seidl R, Cairns N, Lubec G: Expression of apoptosis related
proteins in brains of patients with Alzheimer's disease. Neurosci Lett 2001, 303:79-82.
10.
Paradis E, Douillard H, Koutroumanis M, Goodyer C, LeBlanc A: Amyloid beta peptide of
Alzheimer's disease downregulates Bcl-2 and upregulates bax expression in human neurons.
J Neurosci 1996, 16:7533-7539.
11.
Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C: Transcription factor NF-kappaB
is activated in primary neurons by amyloid beta peptides and in neurons surrounding early
plaques from patients with Alzheimer disease. Proc Natl Acad Sci U S A 1997, 94:2642-2647.
12.
De Strooper B, Beullens M, Contreras B, Levesque L, Craessaerts K, Cordell B, Moechars D,
Bollen M, Fraser P, George-Hyslop PS, Van Leuven F: Phosphorylation, subcellular
localization, and membrane orientation of the Alzheimer's disease-associated presenilins. J
Biol Chem 1997, 272:3590-3598.
13.
Hoerndli FJ, Pelech S, Papassotiropoulos A, Gotz J: Abeta treatment and P301L tau
expression in an Alzheimer's disease tissue culture model act synergistically to promote
aberrant cell cycle re-entry. Eur J Neurosci 2007, 26:60-72.
14.
Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA,
White AR, Hinds MG, Norton RS, et al: Structure of the Alzheimer's disease amyloid
precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J
Biol Chem 2003, 278:17401-17407.
15.
Kong GK, Adams JJ, Cappai R, Parker MW: Structure of Alzheimer's disease amyloid
precursor protein copper-binding domain at atomic resolution. Acta Crystallogr Sect F Struct
Biol Cryst Commun 2007, 63:819-824.
16.
Sheffield LG, Miskiewicz HB, Tannenbaum LB, Mirra SS: Nuclear pore complex proteins in
Alzheimer disease. J Neuropathol Exp Neurol 2006, 65:45-54.
17.
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J,
Johnson-Wood K, et al: Peripherally administered antibodies against amyloid beta-peptide
enter the central nervous system and reduce pathology in a mouse model of Alzheimer
disease. Nat Med 2000, 6:916-919.
18.
Furuta A, Iida T, Nakabeppu Y, Iwaki T: Expression of hMTH1 in the hippocampi of control
and Alzheimer's disease. Neuroreport 2001, 12:2895-2899.
19.
Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH: Recovery of learning and memory is
associated with chromatin remodelling. Nature 2007, 447:178-182.
20.
Fraser PE, Yang DS, Yu G, Levesque L, Nishimura M, Arawaka S, Serpell LC, Rogaeva E, St
George-Hyslop P: Presenilin structure, function and role in Alzheimer disease. Biochim
Biophys Acta 2000, 1502:1-15.
21.
St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman
RG, Pollen D, Drachman D, et al.: The genetic defect causing familial Alzheimer's disease
maps on chromosome 21. Science 1987, 235:885-890.
22.
Nordstedt C, Caporaso GL, Thyberg J, Gandy SE, Greengard P: Identification of the Alzheimer
beta/A4 amyloid precursor protein in clathrin-coated vesicles purified from PC12 cells. J Biol
Chem 1993, 268:608-612.
23.
Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D: Comparison of
neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid
precursor protein and Alzheimer's disease. J Neurosci 1996, 16:5795-5811.
24.
Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM: Extensive
involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J
Neuropathol Exp Neurol 2005, 64:113-122.
25.
Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M,
Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC: Identification of the major Abeta1-42-degrading
catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological
deposition. Nat Med 2000, 6:143-150.
26.
Lotharius J, Brundin P: Pathogenesis of Parkinson's disease: dopamine, vesicles and
alpha-synuclein. Nat Rev Neurosci 2002, 3:932-942.
27.
Wood JG, Mirra SS, Pollock NJ, Binder LI: Neurofibrillary tangles of Alzheimer disease share
antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc Natl
Acad Sci U S A 1986, 83:4040-4043.
28.
David DC, Ittner LM, Gehrig P, Nergenau D, Shepherd C, Halliday G, Gotz J: Beta-amyloid
treatment of two complementary P301L tau-expressing Alzheimer's disease models reveals
similar deregulated cellular processes. Proteomics 2006, 6:6566-6577.
29.
Lipton SA, Gu Z, Nakamura T: Inflammatory mediators leading to protein misfolding and
uncompetitive/fast off-rate drug therapy for neurodegenerative disorders. Int Rev
Neurobiol 2007, 82:1-27.
30.
Tabner BJ, Turnbull S, El-Agnaf O, Allsop D: Production of reactive oxygen species from
aggregating proteins implicated in Alzheimer's disease, Parkinson's disease and other
neurodegenerative diseases. Curr Top Med Chem 2001, 1:507-517.
31.
Zimmermann K, Herget T, Salbaum JM, Schubert W, Hilbich C, Cramer M, Masters CL,
Multhaup G, Kang J, Lemaire HG, et al.: Localization of the putative precursor of Alzheimer's
disease-specific amyloid at nuclear envelopes of adult human muscle. EMBO J 1988,
7:367-372.
32.
Gong CX, Liu F, Grundke-Iqbal I, Iqbal K: Post-translational modifications of tau protein in
Alzheimer's disease. J Neural Transm 2005, 112:813-838.
33.
Rao RV, Ellerby HM, Bredesen DE: Coupling endoplasmic reticulum stress to the cell death
program. Cell Death Differ 2004, 11:372-380.
34.
Milward EA, Papadopoulos R, Fuller SJ, Moir RD, Small D, Beyreuther K, Masters CL: The
amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve
growth factor on neurite outgrowth. Neuron 1992, 9:129-137.
35.
Kowall NW, Kosik KS: Axonal disruption and aberrant localization of tau protein characterize
the neuropil pathology of Alzheimer's disease. Ann Neurol 1987, 22:639-643.
36.
Dineley KT, Westerman M, Bui D, Bell K, Ashe KH, Sweatt JD: Beta-amyloid activates the
mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine
receptors: In vitro and in vivo mechanisms related to Alzheimer's disease. J Neurosci 2001,
21:4125-4133.
37.
Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Murayama Y, Ogata E: Alzheimer amyloid
protein precursor complexes with brain GTP-binding protein G(o). Nature 1993, 362:75-79.
38.
Cutler R, Joseph JA, Yamagami K, Villalobos-Molina R, Roth GS: Area specific alterations in
muscarinic stimulated low Km GTPase activity in aging and Alzheimer's disease:
implications for altered signal transduction. Brain Res 1994, 664:54-60.
39.
Hanger DP, Hughes K, Woodgett JR, Brion JP, Anderton BH: Glycogen synthase kinase-3
induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical
filament epitopes and neuronal localisation of the kinase. Neurosci Lett 1992, 147:58-62.
40.
Berger SL: Histone modifications in transcriptional regulation. Curr Opin Genet Dev 2002,
12:142-148.
41.
Boyd-Kimball D, Castegna A, Sultana R, Poon HF, Petroze R, Lynn BC, Klein JB, Butterfield DA:
Proteomic identification of proteins oxidized by Abeta(1-42) in synaptosomes: implications
for Alzheimer's disease. Brain Res 2005, 1044:206-215.
42.
Yamamoto Y, Gaynor RB: IkappaB kinases: key regulators of the NF-kappaB pathway. Trends
Biochem Sci 2004, 29:72-79.
43.
Mastrogiacomo F, Bergeron C, Kish SJ: Brain alpha-ketoglutarate dehydrogenase complex
activity in Alzheimer's disease. J Neurochem 1993, 61:2007-2014.
44.
He XY, Schulz H, Yang SY: A human brain L-3-hydroxyacyl-coenzyme A dehydrogenase is
identical to an amyloid beta-peptide-binding protein involved in Alzheimer's disease. J Biol
Chem 1998, 273:10741-10746.
45.
Reddy PH, McWeeney S, Park BS, Manczak M, Gutala RV, Partovi D, Jung Y, Yau V, Searles R,
Mori M, Quinn J: Gene expression profiles of transcripts in amyloid precursor protein
transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an
early cellular change in Alzheimer's disease. Hum Mol Genet 2004, 13:1225-1240.
46.
Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E: Overexpression of
tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and
endoplasmic reticulum: implications for Alzheimer's disease. J Cell Biol 1998, 143:777-794.
47.
Lee KY, Clark AW, Rosales JL, Chapman K, Fung T, Johnston RN: Elevated neuronal Cdc2-like
kinase activity in the Alzheimer disease brain. Neurosci Res 1999, 34:21-29.
48.
Lukiw WJ, Bazan NG: Strong nuclear factor-kappaB-DNA binding parallels cyclooxygenase-2
gene transcription in aging and in sporadic Alzheimer's disease superior temporal lobe
neocortex. J Neurosci Res 1998, 53:583-592.
49.
Goedert M, Cohen ES, Jakes R, Cohen P: p42 MAP kinase phosphorylation sites in
microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1.
Implications for Alzheimer's disease [corrected]. FEBS Lett 1992, 312:95-99.
50.
Brinton RD: Cellular and molecular mechanisms of estrogen regulation of memory function
and neuroprotection against Alzheimer's disease: recent insights and remaining challenges.
Learn Mem 2001, 8:121-133.
51.
Kaminska J, Hoffman-Sommer M, Plachta M: [The p24 family proteins--regulators of
vesicular trafficking]. Postepy Biochem, 56:75-82.
52.
Wallace DC: Mitochondrial diseases in man and mouse. Science 1999, 283:1482-1488.
53.
Cassarino DS, Swerdlow RH, Parks JK, Parker WD, Jr., Bennett JP, Jr.: Cyclosporin A increases
resting mitochondrial membrane potential in SY5Y cells and reverses the depressed
mitochondrial membrane potential of Alzheimer's disease cybrids. Biochem Biophys Res
Commun 1998, 248:168-173.
54.
Murrell J, Farlow M, Ghetti B, Benson MD: A mutation in the amyloid precursor protein
associated with hereditary Alzheimer's disease. Science 1991, 254:97-99.
55.
Mehler MF, Mattick JS: Non-coding RNAs in the nervous system. J Physiol 2006,
575:333-341.
56.
Lin MT, Beal MF: Mitochondrial dysfunction and oxidative stress in neurodegenerative
diseases. Nature 2006, 443:787-795.
57.
Lukiw WJ: Micro-RNA speciation in fetal, adult and Alzheimer's disease hippocampus.
Neuroreport 2007, 18:297-300.
58.
Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters
HV, Tabaton M, et al: Mitochondrial abnormalities in Alzheimer's disease. J Neurosci 2001,
21:3017-3023.
59.
Parker WD, Jr., Parks J, Filley CM, Kleinschmidt-DeMasters BK: Electron transport chain
defects in Alzheimer's disease brain. Neurology 1994, 44:1090-1096.
60.
Yao PJ, Zhu M, Pyun EI, Brooks AI, Therianos S, Meyers VE, Coleman PD: Defects in expression
of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer's disease.
Neurobiol Dis 2003, 12:97-109.
61.
Mecocci P, MacGarvey U, Beal MF: Oxidative damage to mitochondrial DNA is increased in
Alzheimer's disease. Ann Neurol 1994, 36:747-751.
62.
Shi J, Zhang S, Tang M, Ma C, Zhao J, Li T, Liu X, Sun Y, Guo Y, Han H, et al: Mutation screening
and association study of the neprilysin gene in sporadic Alzheimer's disease in Chinese
persons. J Gerontol A Biol Sci Med Sci 2005, 60:301-306.
63.
Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS: Kinesin-mediated axonal
transport of a membrane compartment containing beta-secretase and presenilin-1 requires
APP. Nature 2001, 414:643-648.
64.
Kuusisto E, Suuronen T, Salminen A: Ubiquitin-binding protein p62 expression is induced
during apoptosis and proteasomal inhibition in neuronal cells. Biochem Biophys Res
Commun 2001, 280:223-228.
65.
Kuusisto E, Salminen A, Alafuzoff I: Ubiquitin-binding protein p62 is present in neuronal and
glial inclusions in human tauopathies and synucleinopathies. Neuroreport 2001,
12:2085-2090.