Stress Granules Modulate SYK to Cause Microglial Cell Dysfunction in Alzheimer's Disease

EBioMedicine

Volumn 2, Issue 11, 2015, Pages 1785-1798

  Ghosh, Soumitra ^a   Geahlen, Robert L ^a  

^a PURDUE UNIVERSITY   (United States)

Author keywords

Alzheimer's disease; Amyloid beta; Microglial cells; Neurodegenerative disease; Stress granules; SYK tyrosine kinase

Indexed keywords

AMYLOID BETA PROTEIN; ARSENITE SODIUM; CYTOCHALASIN D; FOSTAMATINIB; GAMMA INTERFERON; IMMUNOGLOBULIN G; INTERLEUKIN 1BETA; MONOCYTE CHEMOTACTIC PROTEIN 1; PHOSPHOTYROSINE; PROTEIN KINASE SYK; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN METABOLITE; TAR DNA BINDING PROTEIN; PROTEIN TYROSINE KINASE; SIGNAL PEPTIDE;

ALZHEIMER DISEASE; ANIMAL CELL; ARTICLE; CELL DISRUPTION; CELL GRANULE; CONTROLLED STUDY; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOPRECIPITATION; MICROGLIA; MOUSE; NONHUMAN; PHAGOCYTOSIS; PRIORITY JOURNAL; PROTEIN LOCALIZATION; WESTERN BLOTTING; ANIMAL; BRAIN; CELL LINE; GENE EXPRESSION; GENETICS; IMMUNOHISTOCHEMISTRY; IMMUNOLOGY; KNOCKOUT MOUSE; METABOLISM; PATHOLOGY; PHYSIOLOGICAL STRESS; REPORTER GENE;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; ANIMALS; BRAIN; CELL LINE; CYTOPLASMIC GRANULES; GENE EXPRESSION; GENES, REPORTER; HUMANS; IMMUNOGLOBULIN G; IMMUNOHISTOCHEMISTRY; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICE; MICE, KNOCKOUT; MICROGLIA; PHAGOCYTOSIS; PHOSPHOTYROSINE; PROTEIN-TYROSINE KINASES; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN SPECIES; STRESS, PHYSIOLOGICAL; SYK KINASE;

EID: 84958943092     PISSN: None     EISSN: 23523964     Source Type: Journal    
DOI: 10.1016/j.ebiom.2015.09.053     Document Type: Article

References (82)

1. Anderson P., Kedersha N. Stress granules: the Tao of RNA triage. Trends Biochem. Sci. 2008, 33:141-150.
2. Angata T., Kerr S.C., Greaves D.R., Varki N.M., Crocker P.R., Varki A. Cloning and characterization of human siglec-11: a recently evolved signaling molecule that can interact with SHP-1 and SHP-2 and is expressed by tissue macrophages, including brain microglia. J. Biol. Chem. 2002, 277:24466-24474.
3. Ash P.E., Vanderweyde T.E., Youmans K.L., Apicco D.J., Wolozin B. Pathological stress granules in Alzheimer's disease. Brain Res. 2014, 1584:52-58.
4. Bamberger M.E., Harris M.E., McDonald D.R., Husemann J., Landreth G.E. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J. Neurosci. 2003, 23:2665-2674.
5. Barcia C., Ross C.M., Annese V., Gómez A., Ros-Bernal F., Aguado-Llera D., Martinez-Pagán E., de Pablos V., Fernandez-Villalba E., Herrero M.T. IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease. Cell Death Dis. 2012, 3. 10.1038/cddis.2012.123.
6. Beach T.G., Adler C.H., Sue L.I., Serrano G., Shill H.A., Walker D.G., Lue L., Roher A.E., Dugger B.N., Maarouf C., Birdsill A.C., Intorcia A., Saxon-Labelle M., Pullen J., Scroggins A., Filon J., Scott S., Hoffman B., Garcia A., Caviness J.N., Hentz J.G., Driver-Dunckley E., Jacobson S.A., Davis K.J., Belden C.M., Long K.E., Malek-Ahmadi M., Powell J.J., Gale L.D., Nicholson L.R., Caselli R.J., Woodruff B.K., Rapscak S.Z., Ahern G.L., Shi J., Burke A.D., Reiman E.M., Sabbagh M.N. Arizona study of aging and neurodegenerative disorders and brain and body donation program. Neuropathology 2015, 10.1111/neup.12189.
7. Bertram L., Lange C., Mullin K., Parkinson M., Hsiao M., Hogan M.F., Schjeide B.M., Hooli B., Divito J., Ionita I., Jiang H., Laird N., Moscarillo T., Ohlsen K.L., Elliott K., Wang X., Hu-Lince D., Ryder M., Murphy A., Wagner S.L., Blacker D., Becker K.D., Tanzi R.E. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am. J. Hum. Genet. 2008, 83:623-632.
8. Bianca V.D., Dusi S., Bianchini E., Dal Prà I., Rossi F. Beta-amyloid activates the O-2 forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer's disease. J. Biol. Chem. 1999, 274:15493-15499.
9. Blasi E., Barluzzi R., Mazzolla R., Bistoni F. Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J. Neuroimmunol. 1990, 27:229-237.
10. Buchan J., Parker R. Eukaryotic stress granules: the ins and outs of translation. Mol. Cell 2009, 36:932-941.
11. Buchan J.R., Kolaitis R.-M., Taylor J.P., Parker R. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 2013, 153:1461-1474.
12. Cambier J.C. New nomenclature for the Reth motif (or ARH1/TAM/ARAM/YXXL). Immunol. Today 1995, 16:110.
13. Cameron B., Landreth G. Inflammation, microglia, and Alzheimer's disease. Neurobiol. Dis. 2010, 37:503-509.
14. Combs C.K., Johnson D.E., Cannady S.B., Lehman T.M., Landreth G.E. Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins. J. Neurosci. 1999, 19:928-939.
15. Combs C.K., Karlo J.C., Kao S.C., Landreth G.E. Beta-amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 2001, 21:1179-1188.
16. Crowley M.T., Costello P.S., Fitzer-Attas C.J., Turner M., Meng F., Lowell C., Tybulewicz V.L., DeFranco A.L. A critical role for SYK in signal transduction and phagocytosis mediated by fcγ receptors on macrophages. J. Exp. Med. 1997, 186:1027-1039.
17. Dahlgren K.N., Manelli A.M., Stine W.B., Baker L.K., Krafft G.A., LaDu M.J. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J. Biol. Chem. 2002, 277:32046-32053.
18. Davis J.B., Maher P. Protein kinase C activation inhibits glutamate-induced cytotoxicity in a neuronal cell line. Brain Res. 1994, 652:169-173.
19. Dietrich J., Cella M., Seiffert M., Bühring H.J., Colonna M. Signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells. J. Immunol. 2000, 164:9-12.
20. D'Mello C., Le T., Swain M.G. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factorα signaling during peripheral organ inflammation. J. Neurosci. 2009, 29:2089-2102.
21. Dodel R., Hampel H., Depboylu C., Lin S., Gao F., Schock S., Jäckel S., Wei X., Buerger K., Höft C., Hemmer B., Möller H.J., Farlow M., Oertel W.H., Sommer N., Du Y. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer's disease. Ann. Neurol. 2002, 52:253-256.
22. Dodel R.C., Du Y., Depboylu C., Hampel H., Frölich L., Haag A., Hemmeter U., Paulsen S., Teipel S.J., Brettschneider S., Spottke A., Nölker C., Möller H.J., Wei X., Farlow M., Sommer N., Oertel W.H. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 2004, 75:1472-1474.
23. El Khoury J., Toft M., Hickman S.E., Means T.K., Terada K., Geula C., Luster A.D. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 2007, 13:432-438.
24. Gaikwad S., Larionov S., Wang Y., Dannenberg H., Matozaki T., Monsonego A., Thal D.R., Neumann H. Signal regulatory protein-beta1: a microglial modulator of phagocytosis in Alzheimer's disease. Am. J. Pathol. 2009, 175:2528-2539.
25. Galan J., Paris L.L., Zhang H.-J., Adler J., Geahlen R.L., Tao W.A. Identification of SYK-interacting proteins using a novel amine-specific isotope tag and GFP nanotrap. J. Am. Soc. Mass Spectrom. 2011, 22:319-328.
26. Gandy S., Heppner F.L. Microglia as dynamic and essential components of the amyloid hypothesis. Neuron 2013, 78:575-577.
27. Geahlen R.L. SYK and pTyr'd: signaling through the B cell antigen receptor. Biochim. Biophys. Acta 2009, 1793:1115-1127.
28. Geahlen R.L. Getting Syk: spleen tyrosine kinase as a therapeutic target. Trends Pharmacol. Sci. 2014, 35:414-422.
29. Goggin K., Beaudoin S., Grenier C., Brown A.A., Roucou X. Prion protein aggresomes are poly(A) ribonucleoprotein complexes that induce a PKR-mediated deficient cell stress response. Biochim. Biophys. Acta 2008, 1783:479-491.
30. Griciuc A., Serrano-Pozo A., Parrado A.R., Lesinski A.N., Asselin C.N., Mullin K., Hooli B., Choi S.H., Hyman B.T., Tanzi R.E. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 2013, 78:631-643.
31. Griffin W.S.T. Neuroinflammatory cytokine signaling and Alzheimer's disease. N. Engl. J. Med. 2013, 368:770-771.
32. Guerreiro R., Wojtas A., Bras J., Carrasquillo M., Rogaeva E., Majounie E., Cruchaga C., Sassi C., Kauwe J.S., Younkin S., Hazrati L., Collinge J., Pocock J., Lashley T., Williams J., Lambert J.C., Amouyel P., Goate A., Rademakers R., Morgan K., Powell J., St George-Hyslop P., Singleton A., Hardy J., Alzheimer Genetic Analysis Group TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 2013, 368:117-127.
33. Harris H., Rubinsztein D.C. Control of autophagy as a therapy for neurodegenerative disease. Nat. Rev. Neurol. 2011, 8:108-117.
34. Heit B., Kim H., Cosio G., Castaño D., Collins R., Lowell C.A., Kain K.C., Trimble W.S., Grinstein S. Multimolecular signaling complexes enable SYK-mediated signaling of CD36 internalization. Dev. Cell 2013, 24:372-383.
35. Hickman S.E., Allison E.K., El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci. 2008, 28:8354-8360.
36. Hollingworth P., Harold D., Sims R., Gerrish A., Lambert J.C., Carrasquillo M.M., Abraham R., Hamshere M.L., Pahwa J.S., Moskvina V., et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. 2011, 43:429-435.
37. Huang Y., Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell 2012, 148:1204-1222.
38. Iliuk A.B., Martin V.A., Alicie B.M., Geahlen R.L., Tao W.A. In-depth analyses of kinase-dependent tyrosine phosphoproteomes based on metal ion-functionalized soluble nanopolymers. Mol. Cell. Proteomics 2010, 9:2162-2172.
39. Jay T.R., Miller C.M., Cheng P.J., Graham L.C., Bemiller S., Broihier M.L., Xu G., Margevicius D., Karlo J.C., Sousa G.L., Cotleur A.C., Butovsky O., Bekris L., Staugaitis S.M., Leverenz J.B., Pimplikar S.W., Landreth G.E., Howell G.R., Ransohoff R.M., Lamb B.T. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 2015, 212:287-295.
40. 2 derived from nadph oxidase: a cell culture study. J. Neuroinflammation 2006, 3:24.
41. Jonsson T., Stefansson H., Steinberg S., Jonsdottir I., Jonsson P.V., Snaedal J., Bjornsson S., Huttenlocher J., Levey A.I., Lah J.J., Rujescu D., Hampel H., Giegling I., Andreassen O.A., Engedal K., Ulstein I., Djurovic S., Ibrahim-Verbaas C., Hofman A., Ikram M.A., van Duijn C.M., Thorsteinsdottir U., Kong A., Stefansson K. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 2013, 368:107-116.
42. Keshvara L.M., Isaacson C.C., Yankee T.M., Sarac R., Harrison M.L., Geahlen R.L. SYK- and Lyn-dependent phosphorylation of SYK on multiple tyrosines following B cell activation includes a site that negatively regulates signaling. J. Immunol. 1998, 161:5276-5283.
43. Kiefer F., Brumell J., Al-Alawi N., Latour S., Cheng A., Veillette A., Grinstein S., Pawson T. The SYK protein tyrosine kinase is essential for Fcγ receptor signaling in macrophages and neutrophils. Mol. Cell. Biol. 1998, 18:4209-4220.
44. King O.D., Gitler A.D., Shorter J. The tip of the iceberg: RNA-binding proteins with prion-like Domains in neurodegenerative disease. Brain Res. 2012, 1462:61-80.
45. Koppers M., van Blitterswijk M.M., Vlam L., Rowicka P.A., van Vught P.W., Groen E.J., Spliet W.G., Engelen-Lee J., Schelhaas H.J., de Visser M., van der Kooi A.J., van der Pol W.L., Pasterkamp R.J., Veldink J.H., van den Berg L.H. VCP mutations in familial and sporadic amyotrophic lateral sclerosis. Neurobiol. Aging 2012, 837:e7-e13.
46. Krabbe G., Halle A., Matyash V., Rinnenthal J.L., Eom G.D., Bernhardt U., Miller K.R., Prokop S., Kettenmann H., Heppner F.L. Functional impairment of microglia coincides with beta-amyloid deposition in mice with alzheimer-like pathology. PLoS One 2013, 8.
47. Krisenko M.O., Higgins R.L., Ghosh S., Zhou Q., Trybula J.S., Wang W.-H., Geahlen R.L. Syk is recruited to stress granules and promotes their clearance through autophagy. J. Biol. Chem. 2015, (in press).
48. Lee J.K., Tansey M.G. Microglia isolation from adult mouse brain. Methods Mol. Biol. 2013, 1041:17-23.
49. Linnartz B., Wang Y., Neumann H. Microglial immunoreceptor tyrosine-based activation and inhibition motif signaling in neuroinflammation. Int. J. Alzheimers Dis. 2010, 2010:587463.
50. Liu-Yesucevitz L., Bilgutay A., Zhang Y.J., Vanderweyde T., Citro A., Mehta T., Zaarur N., McKee A., Bowser R., Sherman M., Petrucelli L., Wolozin B. Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One 2010, 5.
51. Loeffler D.A. Intravenous immunoglobulin and Alzheimer's disease: what now?. J. Neuroinflammation 2013, 10:70.
52. McDonald D.R., Bruden K.R., Landreth G.E. Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J. Neurosci. 1997, 17:2284-2294.
53. McEwen E., Kedersha N., Song B., Scheuner D., Gilks N., Han A., Chen J.-J., Anderson P., Kaufman R.J. Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J. Biol. Chem. 2005, 280:16925-16933.
54. Menzies F.M., Fleming A., Rubinsztein D.C. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 2015, 16:345-357.
55. Meyer-Luehmann M., Spires-Jones T.L., Prada C., Garcia-Alloza M., De Calignon A., Rozkalne A., Koenigsknecht-Talboo J., Holtzman D.M., Bacskai B.J., Hyman B.T. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 2008, 451:720-724.
56. Miller Y.I., Choi S.H., Wiesner P., Bae Y.S. The SYK side of TLR4: signalling mechanisms in response to LPS and minimally oxidized LDL. Br. J. Pharmacol. 2012, 167:990-999.
57. Mócsai A., Abram C.L., Jakus Z., Hu Y., Lanier L.L., Lowell C.A. Integrin signaling in neurtrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat. Immunol. 2006, 7:1326-1333.
58. Mosher K.I., Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer's disease. Biochem. Pharmacol. 2014, 88:594-604.
59. Moussaud S., Draheim H.J. A new method to isolate microglia from adult mice and culture them for an Extended period of time. J. Neurosci. Methods 2010, 187:243-253.
60. Naj A.C., Jun G., Beecham G.W., Wang L.S., Vardarajan B.N., Buros J., Gallins P.J., Buxbaum J.D., Jarvik G.P., Crane P.K., et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 2011, 43:436-441.
61. N'Diaye E.N., Branda C.S., Branda S.S., Nevarez L., Colonna M., Lowell C., Hamerman J.A., Seaman W.E. TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J. Cell Biol. 2009, 184:215-223.
62. Neumann M., Sampathu D.M., Kwong L.K., Truax A.C., Micsenyi M.C., Chou T.T., Bruce J., Schuck T., Grossman M., Clark C.M., McCluskey L.F., Miller B.L., Masliah E., Mackenzie I.R., Feldman H., Feiden W., Kretzschmar H.A., Trojanowski J.Q., Lee V.M. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006, 314:130-133.
63. Pan X.D., Zhu Y.G., Lin N., Zhang J., Ye Q.Y., Huang H.P., Chen X.C. Microglial phagocytosis induced by fibrillar beta-amyloid is attenuated by oligomeric beta-amyloid: implications for Alzheimer's disease. Mol. Neurodegener. 2011, 6:45.
64. Paris D., Ait-Ghezala G., Bachmeier C., Laco G., Beaulieu-Abdelahad D., Lin Y., Jin C., Crawford G., Mullan M. The spleen tyrosine kinase (Syk) regulates alzheimer amyloid-β production and Tau hyperphosphorylation. J. Biol. Chem. 2014, 289:33927-33944.
65. Perry G., Cash A.D., Smith M.A. Alzheimer disease and oxidative stress. J. Biomed. Biotechnol. 2002, 2:120-123.
66. Relkin N.R., Szabo P., Adamiak B., Burgut T., Monthe C., Lent R.W., Younkin S., Younkin L., Schiff R., Weksler M.E. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol. Aging 2009, 30:1728-1736.
67. Righi M., Mori L., De Libero G., Sironi M., Biondi A., Mantovani A., Donini S.D., Ricciardi-Castognoii P. Monokine production by microglial cell clones. Eur. J. Immunol. 1989, 19:1443-1448.
68. 2+ signals. J. Biol. Chem. 1993, 268:16688-16692.
69. Solito E., Sastre M. Microglia function in Alzheimer's disease. Front. Pharmacol. 2012, 3:14. 10.3389/fphar.2012.00014.
70. Sondag C.M., Dhawan G., Combs C.K. Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J. Neuroinflammation 2009, 6:1. 10.1186/1742-2094-6-1.
71. Sudduth T.L., Greenstein A., Wilcock D.M. Intracranial Injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers Aβ in APP/PS1 mice along a different time course than anti-Aβ antibodies. Neurobiol. Dis. 2013, 33:9684-9692.
72. Takahashi K., Rochford C.D., Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 2005, 201:647-657.
73. Turner M., Mee P.J., Costello P.S., Williams O., Price A.A., Duddy L.P., Furlong M.T., Geahlen R.L., Tybulewicz V.L.J. Perinatal lethality and a block in the development of B Cells in mice lacking the tyrosine kinase p72SYK. Nature 1995, 378:298-302.
74. Uy B., McGlashan S.R., Shaikh S.B. Measurement of reactive oxygen species in the culture media using Acridan Lumigen PS-3 assay. J. Biomol. Tech. 2011, 22:95-107.
75. Vanderweyde T., Yu H., Varnum M., Liu-Yesucevitz L., Citro A., Ikezu T., Duff K., Wolozin B. Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J. Neurosci. 2012, 32:8270-8283.
76. Vlad S.C., Miller D.R., Kowall N.W., Felson D.T. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 2008, 70:1672-1677.
77. Waelter S., Boeddrich A., Lurz R., Scherzinger E., Lueder G., Lehrach H., Wanker E.E. Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol. Biol. Cell 2001, 12:1393-1407.
78. Wang W.-H., Childress M.O., Geahlen R.L. SYK interacts with and phosphorylates nucleolin to stabilize Bcl-xL mRNA and promote cell survival. Mol. Cell. Biol. 2014, 34:3788-3799.
79. Wang Y., Cella M., Mallinson K., Ulrich J.D., Young K.L., Robinette M.L., Gilfillan S., Krishnan G.M., Sudhakar S., Zinselmeyer B.H., Holtzman D.M., Cirrito J.R., Colonna M. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease Model. Cell 2015, 160:1061-1071.
80. Xue L., Wang W.-H., Iliuk A., Hu L., Galan J.A., Yu S., Hans M., Geahlen R.L., Tao W.A. Sensitive kinase assay linked with phosphoproteomics for identifying direct kinase substrates. Proc. Natl. Acad. Sci. U. S. A. 2012, 109:5615-5620.
81. Yi Y.S., Son Y.-J., Ryou C., Sung G.-H., Kim J.-H., Cho J.Y. Functional roles of SYK in macrophage-mediated inflammatory responses. Mediat. Inflamm. 2014, 2014:270302.
82. Zhang B., Gaiteri C., Bodea L.G., Wang Z., McElwee J., Podtelezhnikov A., Zhang C., Xie T., Tran L., Dobrin R., Fluder E., Clurman B., Melquist S., Narayanan M., Suver C., Shah H., Mahajan M., Gillis T., Mysore J., MacDonald M.E., Lamb J.R., Bennett D.A., Molony C., Stone D.J., Gudnason V., Myers A.J., Schadt E.E., Neumann H., Zhu J., Emilsson V. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 2013, 153:707-720.