Protein-protein interactions underlying the behavioral and psychological symptoms of dementia (BPSD) and Alzheimer’s disease

Autoři: Yimin Mao aff001;  Daniel W. Fisher aff003;  Shuxing Yang aff001;  Rachel M. Keszycki aff003;  Hongxin Dong aff003
Působiště autorů: School of Information and Technology, Jiangxi University of Science and Technology, Jiangxi, China aff001;  Applied Science Institute, Jiangxi University of Science and Technology, Jiangxi, China aff002;  Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article


Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder currently affecting 45 million people worldwide, ranking as the 6th highest cause of death. Throughout the development and progression of AD, over 90% of patients display behavioral and psychological symptoms of dementia (BPSD), with some of these symptoms occurring before memory deficits and therefore serving as potential early predictors of AD-related cognitive decline. However, the biochemical links between AD and BPSD are not known. In this study, we explored the molecular interactions between AD and BPSD using protein-protein interaction (PPI) networks built from OMIM (Online Mendelian Inheritance in Man) genes that were related to AD and two distinct BPSD domains, the Affective Domain and the Hyperactivity, Impulsivity, Disinhibition, and Aggression (HIDA) Domain. Our results yielded 8 unique proteins for the Affective Domain (RHOA, GRB2, PIK3R1, HSPA4, HSP90AA1, GSK3beta, PRKCZ, and FYN), 5 unique proteins for the HIDA Domain (LRP1, EGFR, YWHAB, SUMO1, and EGR1), and 6 shared proteins between both BPSD domains (APP, UBC, ELAV1, YWHAZ, YWHAE, and SRC) and AD. These proteins might suggest specific targets and pathways that are involved in the pathogenesis of these BPSD domains in AD.

Klíčová slova:

Aggression – Alzheimer's disease – Centrality – Dementia – Heat shock response – Pathogenesis – Protein domains – Protein interaction networks


1. Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer's disease. The Lancet. 2016;388(10043):505–17.

2. van der Linde RM, Dening T, Matthews FE, Brayne C. Grouping of behavioural and psychological symptoms of dementia. Int J Geriatr Psychiatry. 2014;29(6):562–8. doi: 10.1002/gps.4037 24677112

3. Kales HC, Lyketsos CG, Miller EM, Ballard C. Management of behavioral and psychological symptoms in people with Alzheimer's disease: an international Delphi consensus. Int Psychogeriatr. 2019;31(1):83–90. doi: 10.1017/S1041610218000534 30068400

4. Gallagher D, Fischer CE, Iaboni A. Neuropsychiatric Symptoms in Mild Cognitive Impairment. Can J Psychiatry. 2017;62(3):161–9. doi: 10.1177/0706743716648296 28212495

5. Paulsen JS, Salmon DP, Thal LJ, Romero R, Weisstein-Jenkins C, Galasko D, et al. Incidence of and risk factors for hallucinations and delusions in patients with probable AD. Neurology. 2000;54(10):1965–71. doi: 10.1212/wnl.54.10.1965 10822438

6. Scarmeas N, Albert M, Brandt J, Blacker D, Hadjigeorgiou G, Papadimitriou A, et al. Motor signs predict poor outcomes in Alzheimer disease. Neurology. 2005;64(10):1696–703. doi: 10.1212/01.WNL.0000162054.15428.E9 15911793

7. Bassiony MM, Steinberg MS, Warren A, Rosenblatt A, Baker AS, Lyketsos CG. Delusions and hallucinations in Alzheimer's disease: prevalence and clinical correlates. Int J Geriatr Psychiatry. 2000;15(2):99–107. doi: 10.1002/(sici)1099-1166(200002)15:2<99::aid-gps82>;2-5 10679840

8. Gaugler JE, Yu F, Krichbaum K, Wyman JF. Predictors of nursing home admission for persons with dementia. Med Care. 2009;47(2):191–8. doi: 10.1097/MLR.0b013e31818457ce 19169120

9. Hart DJ, Craig D, Compton SA, Critchlow S, Kerrigan BM, McIlroy SP, et al. A retrospective study of the behavioural and psychological symptoms of mid and late phase Alzheimer's disease. Int J Geriatr Psychiatry. 2003;18(11):1037–42. doi: 10.1002/gps.1013 14618556

10. Tochimoto S, Kitamura M, Hino S, Kitamura T. Predictors of home discharge among patients hospitalized for behavioural and psychological symptoms of dementia. Psychogeriatrics. 2015;15(4):248–54. doi: 10.1111/psyg.12114 25919794

11. Torrisi M, De Cola MC, Marra A, De Luca R, Bramanti P, Calabrò RS. Neuropsychiatric symptoms in dementia may predict caregiver burden: a Sicilian exploratory study. Psychogeriatrics. 2017;17(2):103–7. doi: 10.1111/psyg.12197 27411501

12. Geda YE, Schneider LS, Gitlin LN, Miller DS, Smith GS, Bell J, et al. Neuropsychiatric symptoms in Alzheimer's disease: past progress and anticipation of the future. Alzheimers Dement. 2013;9(5):602–8. doi: 10.1016/j.jalz.2012.12.001 23562430

13. Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological symptoms of dementia. Front Neurol. 2012;3:73. doi: 10.3389/fneur.2012.00073 22586419

14. Krauthammer M, Kaufmann CA, Gilliam TC, Rzhetsky A. Molecular triangulation: bridging linkage and molecular-network information for identifying candidate genes in Alzheimer's disease. PNAS. 2004;101(42):15148–53. doi: 10.1073/pnas.0404315101 15471992

15. Liu Z-P, Wang Y, Zhang X-S, Chen L. Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer's disease brains. BMC Syst Biol. 2010;4 Suppl 2:S11.

16. Safari-Alighiarloo N, Taghizadeh M, Rezaei-Tavirani M, Goliaei B, Peyvandi AA. Protein-protein interaction networks (PPI) and complex diseases. Gastroenterol Hepatol Bed Bench. 2014;7(1):17–31. 25436094

17. Goñi J, Esteban FJ, de Mendizábal NV, Sepulcre J, Ardanza-Trevijano S, Agirrezabal I, et al. A computational analysis of protein-protein interaction networks in neurodegenerative diseases. BMC Syst Biol. 2008;2:52. doi: 10.1186/1752-0509-2-52 18570646

18. Oti M, Snel B, Huynen MA, Brunner HG. Predicting disease genes using protein-protein interactions. J Med Genet. 2006;43(8):691–8. doi: 10.1136/jmg.2006.041376 16611749

19. Kann MG. Protein interactions and disease: computational approaches to uncover the etiology of diseases. Brief Bioinformatics. 2007;8(5):333–46. doi: 10.1093/bib/bbm031 17638813

20. Schuster-Böckler B, Bateman A. Protein interactions in human genetic diseases. Genome Biol. 2008;9(1):R9. doi: 10.1186/gb-2008-9-1-r9 18199329

21. Navlakha S, Kingsford C. The power of protein interaction networks for associating genes with diseases. Bioinformatics. 2010;26(8):1057–63. doi: 10.1093/bioinformatics/btq076 20185403

22. Nguyen T-P, Ho T-B. Detecting disease genes based on semi-supervised learning and protein-protein interaction networks. Artif Intell Med. 2012;54(1):63–71. doi: 10.1016/j.artmed.2011.09.003 22000346

23. Nguyen T-P, Liu W-c, Jordán F. Inferring pleiotropy by network analysis: linked diseases in the human PPI network. BMC Syst Biol. 2011;5:179. doi: 10.1186/1752-0509-5-179 22034985

24. Nguyen R, Morrissey MD, Mahadevan V, Cajanding JD, Woodin MA, Yeomans JS, et al. Parvalbumin and GAD65 interneuron inhibition in the ventral hippocampus induces distinct behavioral deficits relevant to schizophrenia. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2014;34(45):14948–60.

25. Jeong H, Mason SP, Barabási AL, Oltvai ZN. Lethality and centrality in protein networks. Nature. 2001;411(6833):41–2. doi: 10.1038/35075138 11333967

26. Boyer RS, Moore JS. A Fast String Searching Algorithm. Commun ACM. 1977;20(10):762–72.

27. Li J, Buchner J. Structure, function and regulation of the hsp90 machinery. Biomed J. 2013;36(3):106–17. doi: 10.4103/2319-4170.113230 23806880

28. Sima S, Richter K. Regulation of the Hsp90 system. Biochim Biophys Acta Mol Cell Res. 2018;1865(6):889–97. doi: 10.1016/j.bbamcr.2018.03.008 29563055

29. Kidd M. Paired helical filaments in electron microscopy of Alzheimer's disease. Nature. 1963;197:192–3.

30. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986;261(13):6084–9. 3084478

31. Meraz-Ríos MA, Lira-De León KI, Campos-Peña V, De Anda-Hernández MA, Mena-López R. Tau oligomers and aggregation in Alzheimer's disease. J Neurochem. 2010;112(6):1353–67. doi: 10.1111/j.1471-4159.2009.06511.x 19943854

32. Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nature Reviews Neurology. 2018;14(7):399–415. doi: 10.1038/s41582-018-0013-z 29895964

33. Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem. 1984;259(8):5301–5. 6425287

34. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science (New York, NY). 2005;307(5713):1282–8.

35. Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, et al. Tau reduction prevents Abeta-induced defects in axonal transport. Science (New York, NY). 2010;330(6001):198.

36. Shafiei SS, Guerrero-Muñoz MJ, Castillo-Carranza DL. Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage. Front Aging Neurosci. 2017;9:83. doi: 10.3389/fnagi.2017.00083 28420982

37. Jadhav S, Cubinkova V, Zimova I, Brezovakova V, Madari A, Cigankova V, et al. Tau-mediated synaptic damage in Alzheimer's disease. Transl Neurosci. 2015;6(1):214–26. doi: 10.1515/tnsci-2015-0023 28123806

38. Alonso AD, Cohen LS, Corbo C, Morozova V, ElIdrissi A, Phillips G, et al. Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability. Frontiers in Cellular Neuroscience. 2018;12:338. doi: 10.3389/fncel.2018.00338 30356756

39. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Annals of Neurology. 1991;30(4):572–80. doi: 10.1002/ana.410300410 1789684

40. Arendt T. Synaptic degeneration in Alzheimer's disease. Acta Neuropathol. 2009;118(1):167–79. doi: 10.1007/s00401-009-0536-x 19390859

41. Palop JJ, Mucke L. Amyloid-β Induced Neuronal Dysfunction in Alzheimer’s Disease: From Synapses toward Neural Networks. Nature neuroscience. 2010;13(7):812–8. doi: 10.1038/nn.2583 20581818

42. Canter RG, Penney J, Tsai L-H. The road to restoring neural circuits for the treatment of Alzheimer's disease. Nature. 2016;539(7628):187–96. doi: 10.1038/nature20412 27830780

43. Tata DA, Anderson BJ. The effects of chronic glucocorticoid exposure on dendritic length, synapse numbers and glial volume in animal models: implications for hippocampal volume reductions in depression. Physiology & Behavior. 2010;99(2):186–93.

44. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nature Medicine. 2012;18(9):1413–7. doi: 10.1038/nm.2886 22885997

45. Ota KT, Liu R-J, Voleti B, Maldonado-Aviles JG, Duric V, Iwata M, et al. REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nature Medicine. 2014;20(5):531–5. doi: 10.1038/nm.3513 24728411

46. Duman CH, Duman RS. Spine synapse remodeling in the pathophysiology and treatment of depression. Neuroscience Letters. 2015;601:20–9. doi: 10.1016/j.neulet.2015.01.022 25582786

47. McEwen BS. Stress-induced remodeling of hippocampal CA3 pyramidal neurons. Brain Research. 2016;1645:50–4. doi: 10.1016/j.brainres.2015.12.043 26740399

48. Herbert J, Lucassen PJ. Depression as a risk factor for Alzheimer's disease: Genes, steroids, cytokines and neurogenesis—What do we need to know? Frontiers in Neuroendocrinology. 2016;41:153–71. doi: 10.1016/j.yfrne.2015.12.001 26746105

49. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. 1989;3(4):519–26. doi: 10.1016/0896-6273(89)90210-9 2484340

50. Zabik NL, Imhof MM, Martic-Milne S. Structural evaluations of tau protein conformation: methodologies and approaches. Biochem Cell Biol. 2017;95(3):338–49. doi: 10.1139/bcb-2016-0227 28278386

51. Fontaine SN, Sabbagh JJ, Baker J, Martinez-Licha CR, Darling A, Dickey CA. Cellular factors modulating the mechanism of tau protein aggregation. Cellular and molecular life sciences: CMLS. 2015;72(10):1863–79. doi: 10.1007/s00018-015-1839-9 25666877

52. Medina M, Hernández F, Avila J. New Features about Tau Function and Dysfunction. Biomolecules. 2016;6(2).

53. Liu X-J, Wei J, Shang Y-H, Huang H-C, Lao F-X. Modulation of AβPP and GSK3β by Endoplasmic Reticulum Stress and Involvement in Alzheimer's Disease. J Alzheimers Dis. 2017;57(4):1157–70. doi: 10.3233/JAD-161111 28339396

54. Pei JJ, Tanaka T, Tung YC, Braak E, Iqbal K, Grundke-Iqbal I. Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain. J Neuropathol Exp Neurol. 1997;56(1):70–8. doi: 10.1097/00005072-199701000-00007 8990130

55. Leroy K, Yilmaz Z, Brion JP. Increased level of active GSK-3beta in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol Appl Neurobiol. 2007;33(1):43–55. doi: 10.1111/j.1365-2990.2006.00795.x 17239007

56. Toglia P, Cheung K-H, Mak D-OD, Ullah G. Impaired mitochondrial function due to familial Alzheimer's disease-causing presenilins mutants via Ca(2+) disruptions. Cell Calcium. 2016;59(5):240–50. doi: 10.1016/j.ceca.2016.02.013 26971122

57. Beurel E, Grieco SF, Jope RS. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther. 2015;148:114–31. doi: 10.1016/j.pharmthera.2014.11.016 25435019

58. Jope RS. Glycogen synthase kinase-3 in the etiology and treatment of mood disorders. Front Mol Neurosci. 2011;4:16. doi: 10.3389/fnmol.2011.00016 21886606

59. Marsden WN. Synaptic plasticity in depression: molecular, cellular and functional correlates. Prog Neuropsychopharmacol Biol Psychiatry. 2013;43:168–84. doi: 10.1016/j.pnpbp.2012.12.012 23268191

60. Talman V, Pascale A, Jäntti M, Amadio M, Tuominen RK. Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision-like Proteins? Basic Clin Pharmacol Toxicol. 2016;119(2):149–60. doi: 10.1111/bcpt.12581 27001133

61. Chami B, Steel AJ, De La Monte SM, Sutherland GT. The rise and fall of insulin signaling in Alzheimer's disease. Metab Brain Dis. 2016;31(3):497–515. doi: 10.1007/s11011-016-9806-1 26883429

62. Sulistio YA, Heese K. The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease. Mol Neurobiol. 2016;53(2):905–31. doi: 10.1007/s12035-014-9063-4 25561438

63. Lackie RE, Maciejewski A, Ostapchenko VG, Marques-Lopes J, Choy W-Y, Duennwald ML, et al. The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases. Front Neurosci. 2017;11:254. doi: 10.3389/fnins.2017.00254 28559789

64. Mohamed BA, Barakat AZ, Zimmermann W-H, Bittner RE, Mühlfeld C, Hünlich M, et al. Targeted disruption of Hspa4 gene leads to cardiac hypertrophy and fibrosis. J Mol Cell Cardiol. 2012;53(4):459–68. doi: 10.1016/j.yjmcc.2012.07.014 22884543

65. Zuehlke AD, Beebe K, Neckers L, Prince T. Regulation and function of the human HSP90AA1 gene. Gene. 2015;570(1):8–16. doi: 10.1016/j.gene.2015.06.018 26071189

66. Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet. 2004;13(7):703–14. doi: 10.1093/hmg/ddh083 14962978

67. Dou F, Netzer WJ, Tanemura K, Li F, Hartl FU, Takashima A, et al. Chaperones increase association of tau protein with microtubules. PNAS. 2003;100(2):721–6. doi: 10.1073/pnas.242720499 12522269

68. Jinwal UK, Miyata Y, Koren J, Jones JR, Trotter JH, Chang L, et al. Chemical manipulation of hsp70 ATPase activity regulates tau stability. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2009;29(39):12079–88.

69. Dickey CA, Dunmore J, Lu B, Wang J-W, Lee WC, Kamal A, et al. HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J. 2006;20(6):753–5. doi: 10.1096/fj.05-5343fje 16464956

70. Blair LJ, Nordhues BA, Hill SE, Scaglione KM, O'Leary JC, Fontaine SN, et al. Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Invest. 2013;123(10):4158–69. doi: 10.1172/JCI69003 23999428

71. Matosin N, Halldorsdottir T, Binder EB. Understanding the Molecular Mechanisms Underpinning Gene by Environment Interactions in Psychiatric Disorders: The FKBP5 Model. Biological Psychiatry. 2018;83(10):821–30. doi: 10.1016/j.biopsych.2018.01.021 29573791

72. Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X. An excitatory synapse hypothesis of depression. Trends in Neurosciences. 2015;38(5):279–94. doi: 10.1016/j.tins.2015.03.003 25887240

73. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. PNAS. 1998;95(11):6448–53. doi: 10.1073/pnas.95.11.6448 9600986

74. Chin J, Palop JJ, Puoliväli J, Massaro C, Bien-Ly N, Gerstein H, et al. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2005;25(42):9694–703.

75. Chin J, Palop JJ, Yu G-Q, Kojima N, Masliah E, Mucke L. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2004;24(19):4692–7.

76. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010;142(3):387–97. doi: 10.1016/j.cell.2010.06.036 20655099

77. Ittner A, Chua SW, Bertz J, Volkerling A, van der Hoven J, Gladbach A, et al. Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice. Science (New York, NY). 2016;354(6314):904–8.

78. Lopes S, Vaz-Silva J, Pinto V, Dalla C, Kokras N, Bedenk B, et al. Tau protein is essential for stress-induced brain pathology. PNAS. 2016;113(26):E3755–63. doi: 10.1073/pnas.1600953113 27274066

79. Li J, Zhou H, Ma H, Wei Y, Huang Y, Wu L, et al. Fyn gene polymorphisms contribute to both trait and state anxieties in healthy Chinese-Han individuals. Psychiatr Genet. 2012;22(6):312–3. doi: 10.1097/YPG.0b013e32835862e2 22922807

80. Liang X, Draghi NA, Resh MD. Signaling from integrins to Fyn to Rho family GTPases regulates morphologic differentiation of oligodendrocytes. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2004;24(32):7140–9.

81. Liu H, Nakazawa T, Tezuka T, Yamamoto T. Physical and functional interaction of Fyn tyrosine kinase with a brain-enriched Rho GTPase-activating protein TCGAP. J Biol Chem. 2006;281(33):23611–9. doi: 10.1074/jbc.M511205200 16777849

82. Castañeda P, Muñoz M, García-Rojo G, Ulloa JL, Bravo JA, Márquez R, et al. Association of N-cadherin levels and downstream effectors of Rho GTPases with dendritic spine loss induced by chronic stress in rat hippocampal neurons. J Neurosci Res. 2015;93(10):1476–91. doi: 10.1002/jnr.23602 26010004

83. Fox ME, Chandra R, Menken MS, Larkin EJ, Nam H, Engeln M, et al. Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior. Molecular Psychiatry. 2018.

84. Huesa G, Baltrons MA, Gómez-Ramos P, Morán A, García A, Hidalgo J, et al. Altered distribution of RhoA in Alzheimer's disease and AbetaPP overexpressing mice. J Alzheimers Dis. 2010;19(1):37–56. doi: 10.3233/JAD-2010-1203 20061625

85. Amano M, Kaneko T, Maeda A, Nakayama M, Ito M, Yamauchi T, et al. Identification of Tau and MAP2 as novel substrates of Rho-kinase and myosin phosphatase. J Neurochem. 2003;87(3):780–90. doi: 10.1046/j.1471-4159.2003.02054.x 14535960

86. Shinohara M, Tachibana M, Kanekiyo T, Bu G. Role of LRP1 in the pathogenesis of Alzheimer's disease: evidence from clinical and preclinical studies. J Lipid Res. 2017;58(7):1267–81. doi: 10.1194/jlr.R075796 28381441

87. Mei L, Nave K-A. Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron. 2014;83(1):27–49. doi: 10.1016/j.neuron.2014.06.007 24991953

88. Cau Y, Valensin D, Mori M, Draghi S, Botta M. Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update. Curr Med Chem. 2018;25(1):5–21. doi: 10.2174/0929867324666170426095015 28462702

89. Krumova P, Weishaupt JH. Sumoylation in neurodegenerative diseases. Cellular and molecular life sciences: CMLS. 2013;70(12):2123–38. doi: 10.1007/s00018-012-1158-3 23007842

90. Gallo FT, Katche C, Morici JF, Medina JH, Weisstaub NV. Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc. Front Behav Neurosci. 2018;12.

91. Chen X, Wang C, Zhou S, Li X, Wu L. The Impact of EGFR Gene Polymorphisms on the Risk of Alzheimer's Disease in a Chinese Han Population: A Case-Controlled Study. Med Sci Monit. 2018;24:5035–40. doi: 10.12659/MSM.907809 30026459

92. Shimada T, Fournier AE, Yamagata K. Neuroprotective function of 14-3-3 proteins in neurodegeneration. Biomed Res Int. 2013;2013:564534. doi: 10.1155/2013/564534 24364034

93. Marcelli S, Ficulle E, Iannuzzi F, Kövari E, Nisticò R, Feligioni M. Targeting SUMO-1ylation Contrasts Synaptic Dysfunction in a Mouse Model of Alzheimer's Disease. Mol Neurobiol. 2017;54(8):6609–23. doi: 10.1007/s12035-016-0176-9 27738871

94. Qin X, Wang Y, Paudel HK. Inhibition of Early Growth Response 1 in the Hippocampus Alleviates Neuropathology and Improves Cognition in an Alzheimer Model with Plaques and Tangles. The American Journal of Pathology. 2017;187(8):1828–47. doi: 10.1016/j.ajpath.2017.04.018 28641077

95. Dalley JW, Robbins TW. Fractionating impulsivity: neuropsychiatric implications. Nat Rev Neurosci. 2017;18(3):158–71. doi: 10.1038/nrn.2017.8 28209979

96. Coccaro EF, Sripada CS, Yanowitch RN, Phan KL. Corticolimbic function in impulsive aggressive behavior. Biological Psychiatry. 2011;69(12):1153–9. doi: 10.1016/j.biopsych.2011.02.032 21531387

97. Blair RJR. The Neurobiology of Impulsive Aggression. J Child Adolesc Psychopharmacol. 2016;26(1):4–9. doi: 10.1089/cap.2015.0088 26465707

98. Victoroff J, Lin FV, Coburn KL, Shillcutt SD, Voon V, Ducharme S. Noncognitive Behavioral Changes Associated With Alzheimer's Disease: Implications of Neuroimaging Findings. J Neuropsychiatry Clin Neurosci. 2018;30(1):14–21. doi: 10.1176/appi.neuropsych.16080155 28876969

99. Hoptman MJ. Impulsivity and aggression in schizophrenia: a neural circuitry perspective with implications for treatment. CNS Spectr. 2015;20(3):280–6. doi: 10.1017/S1092852915000206 25900066

100. Leclerc MP, Regenbogen C, Hamilton RH, Habel U. Some neuroanatomical insights to impulsive aggression in schizophrenia. Schizophr Res. 2018;201:27–34. doi: 10.1016/j.schres.2018.06.016 29908715

101. Waltes R, Chiocchetti AG, Freitag CM. The neurobiological basis of human aggression: A review on genetic and epigenetic mechanisms. Am J Med Genet B Neuropsychiatr Genet. 2016;171(5):650–75. doi: 10.1002/ajmg.b.32388 26494515

102. Whelan R, Conrod PJ, Poline J-B, Lourdusamy A, Banaschewski T, Barker GJ, et al. Adolescent impulsivity phenotypes characterized by distinct brain networks. Nature Neuroscience. 2012;15(6):920–5. doi: 10.1038/nn.3092 22544311

103. Šimić G, Babić Leko M, Wray S, Harrington CR, Delalle I, Jovanov-Milošević N, et al. Monoaminergic neuropathology in Alzheimer’s disease. Progress in Neurobiology. 2017;151:101–38. doi: 10.1016/j.pneurobio.2016.04.001 27084356

104. Trillo L, Das D, Hsieh W, Medina B, Moghadam S, Lin B, et al. Ascending monoaminergic systems alterations in Alzheimer's disease. Translating basic science into clinical care. Neuroscience & Biobehavioral Reviews. 2013;37(8):1363–79.

105. Sweet RA, Nimgaonkar VL, Kamboh MI, Lopez OL, Zhang F, DeKosky ST. Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer disease. Arch Neurol. 1998;55(10):1335–40. doi: 10.1001/archneur.55.10.1335 9779662

106. Colzato LS, van den Wildenberg WPM, Van der Does AJW, Hommel B. Genetic markers of striatal dopamine predict individual differences in dysfunctional, but not functional impulsivity. Neuroscience. 2010;170(3):782–8. doi: 10.1016/j.neuroscience.2010.07.050 20678555

107. Eisenberg DTA, MacKillop J, Modi M, Beauchemin J, Dang D, Lisman SA, et al. Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study. Behavioral and Brain Functions. 2007;3(1):2.

108. Benko A, Lazary J, Molnar E, Gonda X, Tothfalusi L, Pap D, et al. Significant association between the C(−1019)G functional polymorphism of the HTR1A gene and impulsivity. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2010;153B(2):592–9.

109. Hakulinen C, Jokela M, Hintsanen M, Merjonen P, Pulkki-Råback L, Seppälä I, et al. Serotonin receptor 1B genotype and hostility, anger and aggressive behavior through the lifespan: the Young Finns study. J Behav Med. 2013;36(6):583–90. doi: 10.1007/s10865-012-9452-y 22945537

110. Zouk H, McGirr A, Lebel V, Benkelfat C, Rouleau G, Turecki G. The effect of genetic variation of the serotonin 1B receptor gene on impulsive aggressive behavior and suicide. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(8):996–1002. doi: 10.1002/ajmg.b.30521 17510950

111. Assal F, Alarcón M, Solomon EC, Masterman D, Geschwind DH, Cummings JL. Association of the serotonin transporter and receptor gene polymorphisms in neuropsychiatric symptoms in Alzheimer disease. Arch Neurol. 2004;61(8):1249–53. doi: 10.1001/archneur.61.8.1249 15313842

112. Jakubczyk A, Wrzosek M, Łukaszkiewicz J, Sadowska-Mazuryk J, Matsumoto H, Śliwerska E, et al. The CC genotype in HTR2A T102C polymorphism is associated with behavioral impulsivity in alcohol-dependent patients. J Psychiatr Res. 2012;46(1):44–9. doi: 10.1016/j.jpsychires.2011.09.001 21930285

113. Bjork JM, Moeller FG, Dougherty DM, Swann AC, Machado MA, Hanis CL. Serotonin 2a receptor T102C polymorphism and impaired impulse control. American Journal of Medical Genetics. 2002;114(3):336–9. doi: 10.1002/ajmg.10206 11920859

114. Lam LCW, Tang NLS, Ma SL, Zhang W, Chiu HFK. 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry. 2004;19(6):523–6. doi: 10.1002/gps.1109 15211529

115. Bevilacqua L, Doly S, Kaprio J, Yuan Q, Tikkanen R, Paunio T, et al. A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature. 2010;468(7327):1061–6. doi: 10.1038/nature09629 21179162

116. Paloyelis Y, Asherson P, Mehta MA, Faraone SV, Kuntsi J. DAT1 and COMT Effects on Delay Discounting and Trait Impulsivity in Male Adolescents with Attention Deficit/Hyperactivity Disorder and Healthy Controls. Neuropsychopharmacology. 2010;35(12):2414–26. doi: 10.1038/npp.2010.124 20736997

117. Sonuga-Barke EJS, Kumsta R, Schlotz W, Lasky-Su J, Marco R, Miranda A, et al. A Functional Variant of the Serotonin Transporter Gene (SLC6A4) Moderates Impulsive Choice in Attention-Deficit/Hyperactivity Disorder Boys and Siblings. Biological Psychiatry. 2011;70(3):230–6. doi: 10.1016/j.biopsych.2011.01.040 21497794

118. Haberstick BC, Smolen A, Hewitt JK. Family-based association test of the 5HTTLPR and aggressive behavior in a general population sample of children. Biological Psychiatry. 2006;59(9):836–43. doi: 10.1016/j.biopsych.2005.10.008 16412987

119. Reif A, Rösler M, Freitag CM, Schneider M, Eujen A, Kissling C, et al. Nature and nurture predispose to violent behavior: serotonergic genes and adverse childhood environment. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology. 2007;32(11):2375–83.

120. Manuck SB, Flory JD, Ferrell RE, Mann JJ, Muldoon MF. A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity. Psychiatry Research. 2000;95(1):9–23. doi: 10.1016/s0165-1781(00)00162-1 10904119

121. Frazzetto G, Di Lorenzo G, Carola V, Proietti L, Sokolowska E, Siracusano A, et al. Early trauma and increased risk for physical aggression during adulthood: the moderating role of MAOA genotype. PLoS ONE. 2007;2(5):e486. doi: 10.1371/journal.pone.0000486 17534436

122. Kuepper Y, Grant P, Wielpuetz C, Hennig J. MAOA-uVNTR genotype predicts interindividual differences in experimental aggressiveness as a function of the degree of provocation. Behavioural Brain Research. 2013;247:73–8. doi: 10.1016/j.bbr.2013.03.002 23499704

123. Soeiro-De-Souza MG, Stanford MS, Bio DS, Machado-Vieira R, Moreno RA. Association of the COMT Met1⁵⁸ allele with trait impulsivity in healthy young adults. Mol Med Rep. 2013;7(4):1067–72. doi: 10.3892/mmr.2013.1336 23440431

124. Rujescu D, Giegling I, Gietl A, Hartmann AM, Möller H-J. A functional single nucleotide polymorphism (V158M) in the COMT gene is associated with aggressive personality traits. Biological Psychiatry. 2003;54(1):34–9. doi: 10.1016/s0006-3223(02)01831-0 12842306

125. Perez-Rodriguez MM, Weinstein S, New AS, Bevilacqua L, Yuan Q, Zhou Z, et al. Tryptophan-hydroxylase 2 haplotype association with borderline personality disorder and aggression in a sample of patients with personality disorders and healthy controls. J Psychiatr Res. 2010;44(15):1075–81. doi: 10.1016/j.jpsychires.2010.03.014 20451217

126. Parvizi J, Van Hoesen GW, Damasio A. The selective vulnerability of brainstem nuclei to Alzheimer's disease. Annals of Neurology. 2001;49(1):53–66. doi: 10.1002/1531-8249(200101)49:1<53::aid-ana30>;2-q 11198297

127. Lyness SA, Zarow C, Chui HC. Neuron loss in key cholinergic and aminergic nuclei in Alzheimer disease: a meta-analysis. Neurobiol Aging. 2003;24(1):1–23. doi: 10.1016/s0197-4580(02)00057-x 12493547

128. D'Amelio M, Puglisi-Allegra S, Mercuri N. The role of dopaminergic midbrain in Alzheimer's disease: Translating basic science into clinical practice. Pharmacol Res. 2018;130:414–9. doi: 10.1016/j.phrs.2018.01.016 29391234

129. Nobili A, Latagliata EC, Viscomi MT, Cavallucci V, Cutuli D, Giacovazzo G, et al. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun. 2017;8:14727. doi: 10.1038/ncomms14727 28367951

130. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59. doi: 10.1007/bf00308809 1759558

131. de Jong LW, Ferrarini L, van der Grond J, Milles JR, Reiber JHC, Westendorp RGJ, et al. Shape abnormalities of the striatum in Alzheimer's disease. J Alzheimers Dis. 2011;23(1):49–59. doi: 10.3233/JAD-2010-101026 20930298

132. Fuentealba RA, Liu Q, Kanekiyo T, Zhang J, Bu G. Low density lipoprotein receptor-related protein 1 promotes anti-apoptotic signaling in neurons by activating Akt survival pathway. J Biol Chem. 2009;284(49):34045–53. doi: 10.1074/jbc.M109.021030 19815552

133. Bruban J, Voloudakis G, Huang Q, Kajiwara Y, Al Rahim M, Yoon Y, et al. Presenilin 1 is necessary for neuronal, but not glial, EGFR expression and neuroprotection via γ-secretase-independent transcriptional mechanisms. FASEB J. 2015;29(9):3702–12. doi: 10.1096/fj.15-270645 25985800

134. Lee YJ, Castri P, Bembry J, Maric D, Auh S, Hallenbeck JM. SUMOylation participates in induction of ischemic tolerance. J Neurochem. 2009;109(1):257–67. doi: 10.1111/j.1471-4159.2009.05957.x 19200349

135. Veyrac A, Gros A, Bruel-Jungerman E, Rochefort C, Kleine Borgmann FB, Jessberger S, et al. Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning. PNAS. 2013;110(17):7062–7. doi: 10.1073/pnas.1220558110 23569253

136. Iwakura Y, Zheng Y, Sibilia M, Abe Y, Piao Y-S, Yokomaku D, et al. Qualitative and quantitative re-evaluation of epidermal growth factor-ErbB1 action on developing midbrain dopaminergic neurons in vivo and in vitro: target-derived neurotrophic signaling (Part 1). J Neurochem. 2011;118(1):45–56. doi: 10.1111/j.1471-4159.2011.07287.x 21517852

137. Sekiguchi H, Iritani S, Habuchi C, Torii Y, Kuroda K, Kaibuchi K, et al. Impairment of the tyrosine hydroxylase neuronal network in the orbitofrontal cortex of a genetically modified mouse model of schizophrenia. Brain Research. 2011;1392:47–53. doi: 10.1016/j.brainres.2011.03.058 21458426

138. Ding H, Underwood R, Lavalley N, Yacoubian TA. 14-3-3 inhibition promotes dopaminergic neuron loss and 14-3-3θ overexpression promotes recovery in the MPTP mouse model of Parkinson's disease. Neuroscience. 2015;307:73–82. doi: 10.1016/j.neuroscience.2015.08.042 26314634

139. Xu J, Kao S-Y, Lee FJS, Song W, Jin L-W, Yankner BA. Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nature Medicine. 2002;8(6):600–6. doi: 10.1038/nm0602-600 12042811

140. Kneynsberg A, Combs B, Christensen K, Morfini G, Kanaan NM. Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms. Front Neurosci. 2017;11:572. doi: 10.3389/fnins.2017.00572 29089864

141. Honer WG. Pathology of presynaptic proteins in Alzheimer's disease: more than simple loss of terminals. Neurobiol Aging. 2003;24(8):1047–62. doi: 10.1016/j.neurobiolaging.2003.04.005 14643376

142. Bae JR, Kim SH. Synapses in neurodegenerative diseases. BMB Rep. 2017;50(5):237–46. doi: 10.5483/BMBRep.2017.50.5.038 28270301

143. Arendt T. Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization. Neuroscience. 2001;102(4):723–65. doi: 10.1016/s0306-4522(00)00516-9 11182240

144. Matsuo M, Campenot RB, Vance DE, Ueda K, Vance JE. Involvement of low-density lipoprotein receptor-related protein and ABCG1 in stimulation of axonal extension by apoE-containing lipoproteins. Biochim Biophys Acta. 2011;1811(1):31–8. doi: 10.1016/j.bbalip.2010.10.004 21040802

145. Qiu Z, Hyman BT, Rebeck GW. Apolipoprotein E receptors mediate neurite outgrowth through activation of p44/42 mitogen-activated protein kinase in primary neurons. J Biol Chem. 2004;279(33):34948–56. doi: 10.1074/jbc.M401055200 15169786

146. Yoon C, Van Niekerk EA, Henry K, Ishikawa T, Orita S, Tuszynski MH, et al. Low-density lipoprotein receptor-related protein 1 (LRP1)-dependent cell signaling promotes axonal regeneration. J Biol Chem. 2013;288(37):26557–68. doi: 10.1074/jbc.M113.478552 23867460

147. Merino P, Diaz A, Yepes M. Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) promote neurorepair in the ischemic brain. Receptors Clin Investig. 2017;4(2). 28804736

148. Leung JYK, Bennett WR, King AE, Chung RS. The impact of metallothionein-II on microglial response to tumor necrosis factor-alpha (TNFα) and downstream effects on neuronal regeneration. J Neuroinflammation. 2018;15(1):56. doi: 10.1186/s12974-018-1070-3 29471847

149. Cheng P, Chen K, Yu W, Gao S, Hu S, Sun X, et al. Protein phosphatase 2A (PP2A) activation promotes axonal growth and recovery in the CNS. Journal of the Neurological Sciences. 2015;359(1–2):48–56. doi: 10.1016/j.jns.2015.10.025 26671085

150. Joy MT, Vrbova G, Dhoot GK, Anderson PN. Sulf1 and Sulf2 expression in the nervous system and its role in limiting neurite outgrowth in vitro. Exp Neurol. 2015;263:150–60. doi: 10.1016/j.expneurol.2014.10.011 25448158

151. Leinster VHL, Joy MT, Vuononvirta RE, Bolsover SR, Anderson PN. ErbB1 epidermal growth factor receptor is a valid target for reducing the effects of multiple inhibitors of axonal regeneration. Exp Neurol. 2013;239:82–90. doi: 10.1016/j.expneurol.2012.09.007 23022459

152. Zschätzsch M, Oliva C, Langen M, De Geest N, Ozel MN, Williamson WR, et al. Regulation of branching dynamics by axon-intrinsic asymmetries in Tyrosine Kinase Receptor signaling. Elife. 2014;3:e01699. doi: 10.7554/eLife.01699 24755286

153. Kaplan A, Kent CB, Charron F, Fournier AE. Switching responses: spatial and temporal regulators of axon guidance. Mol Neurobiol. 2014;49(2):1077–86. doi: 10.1007/s12035-013-8582-8 24271658

154. Kaplan A, Morquette B, Kroner A, Leong S, Madwar C, Sanz R, et al. Small-Molecule Stabilization of 14-3-3 Protein-Protein Interactions Stimulates Axon Regeneration. Neuron. 2017;93(5):1082–93.e5. doi: 10.1016/j.neuron.2017.02.018 28279353

155. Yam PT, Kent CB, Morin S, Farmer WT, Alchini R, Lepelletier L, et al. 14-3-3 proteins regulate a cell-intrinsic switch from sonic hedgehog-mediated commissural axon attraction to repulsion after midline crossing. Neuron. 2012;76(4):735–49. doi: 10.1016/j.neuron.2012.09.017 23177959

156. Joo Y, Schumacher B, Landrieu I, Bartel M, Smet-Nocca C, Jang A, et al. Involvement of 14-3-3 in tubulin instability and impaired axon development is mediated by Tau. FASEB J. 2015;29(10):4133–44. doi: 10.1096/fj.14-265009 26103986

157. van Niekerk EA, Willis DE, Chang JH, Reumann K, Heise T, Twiss JL. Sumoylation in axons triggers retrograde transport of the RNA-binding protein La. PNAS. 2007;104(31):12913–8. doi: 10.1073/pnas.0611562104 17646655

158. Tang LTH, Craig TJ, Henley JM. SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation. Nat Commun. 2015;6:7728. doi: 10.1038/ncomms8728 26173895

159. Girach F, Craig Tim J, Rocca Daniel L, Henley Jeremy M. RIM1α SUMOylation Is Required for Fast Synaptic Vesicle Exocytosis. Cell Rep. 2013;5(5):1294–301. doi: 10.1016/j.celrep.2013.10.039 24290762

160. Ghosh H, Auguadri L, Battaglia S, Simone Thirouin Z, Zemoura K, Messner S, et al. Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission. Nat Commun. 2016;7.

161. Levkovitz Y, Baraban JM. A dominant negative Egr inhibitor blocks nerve growth factor-induced neurite outgrowth by suppressing c-Jun activation: role of an Egr/c-Jun complex. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2002;22(10):3845–54.

162. Ravni A, Vaudry D, Gerdin MJ, Eiden MV, Falluel-Morel A, Gonzalez BJ, et al. A cAMP-dependent, protein kinase A-independent signaling pathway mediating neuritogenesis through Egr1 in PC12 cells. Mol Pharmacol. 2008;73(6):1688–708. doi: 10.1124/mol.107.044792 18362103

163. Chasseigneaux S, Dinc L, Rose C, Chabret C, Coulpier F, Topilko P, et al. Secreted amyloid precursor protein β and secreted amyloid precursor protein α induce axon outgrowth in vitro through Egr1 signaling pathway. PLoS ONE. 2011;6(1):e16301. doi: 10.1371/journal.pone.0016301 21298006

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden