Molecular Biology

, Volume 53, Issue 2, pp 176–191 | Cite as

The Major Human Stress Protein Hsp70 as a Factor of Protein Homeostasis and a Cytokine-Like Regulator

  • D. G. GarbuzEmail author
  • O. G. Zatsepina
  • M. B. Evgen’ev


Heat shock proteins (HSPs) are important factors of protein homeostasis and possess chaperone properties, providing for a folding and intracellular transport of proteins and facilitating the recovery or utilization of proteins partly denatured on exposure to various stress factors. Proteins of the Hsp70 family are the most universal molecular chaperones and interact with the greatest number of protein substrates. Several proteins of the Hsp70 family are released into the extracellular space, where they play an important role in intercellular communications and act as alarmins, or “danger signals,” to modulate the immune response. The secreted Hsp70 can additionally act as an effective neuroprotector, increasing the survival of neurons in various proteinopathies, as has been demonstrated in Alzheimer’s and Parkinson’s disease models. In this regard, recombinant Hsp70 and inducers of endogenous Hsp70 synthesis may be considered as candidate therapeutics with immune-modulating and neuroprotective properties.


recombinant Hsp70 stress neuroprotection protein homeostasis 



  1. 1.
    Laskey R.A., Honda B.M., Mills A.D., Finch J.T. 1978. Nucleosomes are assembled by an acidic protein which binds histones and transfers them to DNA. Nature. 275, 416–420.CrossRefPubMedGoogle Scholar
  2. 2.
    Mayer M.P. 2010. Gymnastics of molecular chaperones. Mol. Cell. 39, 321–331.CrossRefPubMedGoogle Scholar
  3. 3.
    Craig E.A., Jacobsen K. 1984. Mutations of the heat inducible 70 kilodalton genes of yeast confer temperature sensitive growth. Cell. 38, 841–849.CrossRefPubMedGoogle Scholar
  4. 4.
    Feder M.E., Hofmann G.E. 1999. Heat-shock proteins, molecular chaperones, and the stress response: Evolutionary and ecological physiology. Annu. Rev. Physiol. 61, 243–282.CrossRefPubMedGoogle Scholar
  5. 5.
    Barua D., Heckathorn S.A. 2004. Acclimation of the temperature set-points of the heat-shock response. J. Therm. Biol. 29, 185–193.CrossRefGoogle Scholar
  6. 6.
    Gong W.J., Golic K.G. 2006. Loss of Hsp70 in Drosophila is pleiotropic, with effects on thermotolerance, recovery from heat shock and neurodegeneration. Genetics. 172, 275–286.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Evgen’ev M.B., Garbuz D.G., Zatsepina O.G. 2014. Heat Shock Proteins and Whole Body Adaptation to Extreme Environments. Dordrecht, Netherlands: Springer.CrossRefGoogle Scholar
  8. 8.
    Kampinga H.H., Hageman J., Vos M.J., Kubota H., anguay R.M., Bruford E.A., Cheetham M.E., Chen B., Hightower L.E. 2009. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones. 14, 105–111.CrossRefPubMedGoogle Scholar
  9. 9.
    Evgen’ev M.B., Garbuz D.G., Zatsepina O.G. 2005. Heat shock proteins: Functions and role in adaptation to hyperthermia. Ontogenez. 36, 265–273.PubMedGoogle Scholar
  10. 10.
    Hartl F.U., Bracher A., Hayer-Hartl M. 2011. Molecular chaperones in protein folding and proteostasis. Nature. 475, 324–332.CrossRefPubMedGoogle Scholar
  11. 11.
    Zatsepina O.G., Przhiboro A.A., Yushenova I.A., Shilova V., Zelentsova E.S., Shostak N.G., Evgen’ev M.B., Garbuz D.G. 2016. A Drosophila heat shock response represents an exception rather than a rule among Diptera species. Insect. Mol. Biol. 25, 431–449.CrossRefPubMedGoogle Scholar
  12. 12.
    Asea A., Rehli M., Kabingu E., Boch A., Bare O., Auron P.E., Stevenson M.A., Calderwood S.K. 2002. Novel signal transduction pathway utilized by extracellular HSP70: Role of toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 277, 15028‒15034.CrossRefPubMedGoogle Scholar
  13. 13.
    Calderwood S.K., Mambula S.S., Gray P.J., Jr., Theriault J.R. 2007. Extracellular heat shock proteins in cell signaling. FEBS Lett. 581, 3689–3694.CrossRefPubMedGoogle Scholar
  14. 14.
    Ghosh A.K., Sinha D., Mukherjee S., Biswas R., Biswas T. 2015. LPS stimulates and Hsp70 down-regulates TLR4 to orchestrate differential cytokine response of culture-differentiated innate memory CD8+ T cells. Cytokine. 73, 44‒52.CrossRefPubMedGoogle Scholar
  15. 15.
    Kakimura J., Kitamura Y., Takata K., Umeki M., Suzuki S., Shibagaki K., Taniguchi T., Nomura Y., Gebicke-Haerter P.J., Smith M.A., Perry G., Shimohama S. 2002. Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. FASEB J. 16, 601–603.CrossRefPubMedGoogle Scholar
  16. 16.
    Guzhova I., Kislyakova K., Moskaliova O., Fridlanskaya I., Tytell M., Cheetham M., Margulis B. 2001. In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stresstolerance. Brain Res. 914, 66–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Bobkova N.V., Garbuz D.G., Nesterova I., Medvinskaya N., Samokhin A., Alexandrova I., Yashin V., Karpov V., Kukharsky M.S., Ninkina N.N., Smirnov A.A., Nudler E., Evgen’ev M. 2014. Therapeutic effect of exogenous Hsp70 in mouse models of Alzheimer’s disease. J. Alzheimers Dis. 38, 425–435.CrossRefPubMedGoogle Scholar
  18. 18.
    Evgen’ev M.B., Krasnov G.S., Nesterova I.V., Garbuz D.G., Karpov V.L., Morozov A.V., Snezhkina A.V., Samokhin A.N., Sergeev A., Kulikov A.M., Bobkova N.V. 2017. Molecular mechanisms underlying neuroprotective effect of intranasal administration of human Hsp70 in mouse model of Alzheimer’s disease. J. Alzheimers Dis. 59, 1415‒1426.CrossRefPubMedGoogle Scholar
  19. 19.
    De Mena L., Chhangani D., Fernandez-Funez P., Rincon-Limas D.E. 2017. secHsp70 as a tool to approach amyloid-β42 and other extracellular amyloids. Fly. 11, 179‒184.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Milner C.M., Campbell R.D. 1990. Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics. 32, 242–251.CrossRefPubMedGoogle Scholar
  21. 21.
    Milner C.M., Campbell R.D. 1992. Polymorphic analysis of three MHC-linked HSP70 genes. Immunogenetics. 36, 357–362.CrossRefPubMedGoogle Scholar
  22. 22.
    Walter L., Rauh F., Gunther E. 1994. Comparative analysis of the three major histocompatibility complex-linked heat shock protein 70 (hsp70) genes of the rat. Immunogenetics. 40, 325–330.CrossRefPubMedGoogle Scholar
  23. 23.
    Garbuz D.G., Astakhova L.N., Zatsepina O.G., Arkhipova I.R., Nudler E., Evgen’ev M.B. 2011. Functional organization of hsp70 cluster in camel (Camelus dromedarius) and other mammals. PLoS One. 6, e27205.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hess K., Oliverio R., Nguyen P., Le D., Ellis J., Kdeiss B., Ord S., Chalkia D., Nikolaidis N. 2018. Concurrent action of purifying selection and gene conversion results in extreme conservation of the major stress-inducible Hsp70 genes in mammals. Sci. Rep. 8, 5082.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Flaherty K.M., DeLuca-Flaherty C., McKay D.B. 1990. Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein. Nature. 346, 623–628.CrossRefPubMedGoogle Scholar
  26. 26.
    Flajnik M.F., Canel C., Kramer J., Kasahara M. 1991. Which came first, MHC class I or class II? Immunogenetics. 33, 295–300.CrossRefPubMedGoogle Scholar
  27. 27.
    Welch W.J., Feramisco J.R. 1985. Rapid purification of mammalian 70 000-dalton stress proteins: Affinity of the proteins for nucleotides. Mol. Cell. Biol. 5, 1229–1237.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Nollen E.A., Morimoto R.I. 2002. Chaperoning signaling pathways: Molecular chaperones as stress-sensing ‘heat shock’ proteins. J. Cell Sci. 2002. 115, 2809–2816.PubMedGoogle Scholar
  29. 29.
    Guzhova I., Margulis B. 2006. Hsp70 chaperone as a survival factor in cell pathology. Int. Rev. Cytol. 254, 101‒149.CrossRefPubMedGoogle Scholar
  30. 30.
    Frydman J. 2001. Folding of newly translated proteins in vivo: The role of molecular chaperones. Annu. Rev. Biochem. 70, 603–647.CrossRefPubMedGoogle Scholar
  31. 31.
    Goloubinoff P., Sassi A.S., Fauvet B., Barducci A., De Los Rios P. 2018. Chaperones convert the energy from ATP into the nonequilibrium stabilization of native proteins. Nature Chem. Biol. 14, 388–395.CrossRefGoogle Scholar
  32. 32.
    Chakraborty K., Chatila M., Sinha J., Shi Q., Poschner B.C., Sikor M., Jiang G., Lamb D.C., Hartl F.U., Hayer-Hartl M. 2010. Chaperonin-catalyzed rescue of kinetically trapped states in protein folding. Cell. 142, 112‒122.CrossRefPubMedGoogle Scholar
  33. 33.
    Reeg S., Jung T., Castro J.P., Davies K.J.A., Henze A., Grune T. 2016. The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome. Free Radic. Biol. Med. 99, 153‒166.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bercovich B., Stancovski I., Mayer A., Blumenfeld N., Laszlo A., Schwartz A.L., Ciechanover A. 1997. Ubiquitin-dependent degradation of certain protein substrates in vitro requires the molecular chaperone Hsc70. J. Biol. Chem. 272, 9002–9010.CrossRefPubMedGoogle Scholar
  35. 35.
    Nelson R.J., Ziegelhoffer T., Nicolet C., Werner-Washburne M., Craig E.A. 1992. The translation machinery and 70 kD heat shock protein cooperate in protein synthesis. Cell. 71, 97–105.CrossRefPubMedGoogle Scholar
  36. 36.
    Ku Z., Yang J., Menon V., Thomason D.B. 1995. Decreased polysomal HSP70 may slow polypeptide elongation during skeletal muscle atrophy. Am. J. Physiol. 268, 1369–1374.CrossRefGoogle Scholar
  37. 37.
    Arias E., Cuervo A.M. 2011. Chaperone-mediated autophagy in protein quality control. Curr. Opin. Cell Biol. 23, 184–189.CrossRefPubMedGoogle Scholar
  38. 38.
    Fan A.C., Young J.C. 2011. Function of cytosolic chaperones in Tom70-mediated mitochondrial import. Protein Pept. Lett. 18, 122‒131.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Sousa R., Lafer E.M. 2006. Keep the traffic moving: mechanism of the Hsp70 motor. Traffic. 7, 1596‒1603.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kutik S., Guiard B., Meyer H.E., Wiedemann N., Pfanner N. 2007. Cooperation of translocase complexes in mitochondrial protein import. J. Cell Biol. 179, 585‒591.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    van der Laan M., Hutu D.P., Rehling P. 2010. On the mechanism of preprotein import by the mitochondrial presequence translocase. Biochim. Biophys. Acta. 1803, 732‒739.CrossRefPubMedGoogle Scholar
  42. 42.
    Hamman B.D., Hendershot L.M., Johnson A.E. 1998. BiP maintains the permeability barrier of the ER membrane by sealing the lumenal end of the translocon pore before and early in translocation. Cell. 92, 747–758.CrossRefPubMedGoogle Scholar
  43. 43.
    Dudek J., Pfeffer S., Lee P.H., Jung M., Cavalié A., Helms V., Förster F., Zimmermann R. 2015. Protein transport into the human endoplasmic reticulum. J. Mol. Biol. 427, 1159‒1175.CrossRefPubMedGoogle Scholar
  44. 44.
    Melnick J., Argon Y. 1995. Molecular chaperones and the biosynthesis of antigen receptors. Immunol. Today. 16, 243–250.CrossRefPubMedGoogle Scholar
  45. 45.
    Sawa T., Imamura T., Haruta T., Sasaoka T., Ishiki M., Takata Y., Takada Y., Morioka H., Ishihara H., Usui I., Kobayashi M. 1996. Hsp70 family molecular chaperones and mutant insulin receptor: Differential binding specificities of BiP and Hsp70/Hsc70 determines accumulation or degradation of insulin receptor. Biochem. Biophys. Res. Commun. 218, 449–453.CrossRefPubMedGoogle Scholar
  46. 46.
    Plemper R.K., Böhmler S., Bordallo J., Sommer T., Wolf D.H. 1997. Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature. 388, 891–895.CrossRefPubMedGoogle Scholar
  47. 47.
    Nishikawa S., Brodsky J.L., Nakatsukasa K. 2005. Roles of molecular chaperones in endoplasmic reticulum (ER. quality control and ER-associated degradation (ERAD). J. Biochem. 137, 551–555.CrossRefPubMedGoogle Scholar
  48. 48.
    Lasunskaia E.B., Fridlianskaia I.I., Guzhova I.V., Bozhkov V.M., Margulis B.A. 1997. Accumulation of major stress protein 70 kDa protects myeloid and lymphoid cells from death by apoptosis. Apoptosis. 2, 156–163.CrossRefPubMedGoogle Scholar
  49. 49.
    Takano M., Arai T., Mokuno Y., Nishimura H., Nimura Y., Yoshikai Y. 1998. Dibutyryl cyclic adenosine monophosphate protects mice against tumor necrosis factor-alpha-induced hepatocyte apoptosis accompanied by increased heat shock protein 70 expression. Cell Stress Chaperones. 3, 109–117.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Ahn J.H., Ko Y.G., Park W.Y., Kang Y.S., Chung H.Y., Seo J.S. 1999. Suppression of ceramide-mediated apoptosis by HSP70. Mol. Cells. 9, 200–206.PubMedGoogle Scholar
  51. 51.
    Brar B.K., Stephanou A., Wagstaff M.J., Coffin R.S., Marber M.S., Engelmann G., Latchman D.S. 1999. Heat shock proteins delivered with a virus vector can protect cardiac cells against apoptotic as well as against thermal or hypoxic stress. J. Mol. Cell. Cardiol. 31, 135–146.CrossRefPubMedGoogle Scholar
  52. 52.
    Wagstaff M.J., Collaço-Moraes Y., Smith J., de Belleroche J.S., Coffin R.S., Latchman D.S. 1999. Protection of neuronal cells from apoptosis by HSP27 delivered with a herpes simplex virus-based vector. J. Biol. Chem. 274, 5061–5069.CrossRefPubMedGoogle Scholar
  53. 53.
    Kumar S., Stokes J. 3rd, Singh U.P., Scissum Gunn K., Acharya A., Manne U., Mishra M. 2016. Targeting Hsp70: A possible therapy for cancer. Cancer Lett. 374, 156–166.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Pandey M.K., Prasad S., Tyagi A.K., Deb L., Huang J., Karelia D.N., Amin S.G., Aggarwal B.B. 2016. Targeting cell survival proteins for cancer cell death. Pharmaceuticals. 9, e11.CrossRefPubMedGoogle Scholar
  55. 55.
    Sharp F.R., Zhan X., Liu D.Z. 2013. Heat shock proteins in the brain: Role of Hsp70, Hsp27, and HO-1 (Hsp32) and their therapeutic potential. Transl. Stroke Res. 4, 685‒692.CrossRefPubMedGoogle Scholar
  56. 56.
    Schett G., Steiner C.W., Gröger M., Winkler S., Graninger W., Smolen J., Xu Q., Steiner G. 1999. Activation of Fas inhibits heat-induced activation of HSF1 and up-regulation of HSP70. FASEB J. 13, 833–842.CrossRefPubMedGoogle Scholar
  57. 57.
    Mosser D.D., Caron A.W., Bourged L., Denis-Larose C., Massie B. 1997. Role of the human heat shock protein HSP70 in protection against stress-induced apoptosis. Mol. Cell. Biol. 17, 5317–5327.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Gabai V.L., Meriin A.B., Yaglom J.A., Volloch V., Sherman M.Y. 1998. Role of HSP70 in regulation of stress-kinase JNK: Implications in apoptosis and aging. FEBS Lett. 438, 1–4.CrossRefPubMedGoogle Scholar
  59. 59.
    Kumar Y., Tatu U. 2003. Stress protein flux during recovery from simulated ischemia: Induced heat shock protein 70 confers cytoprotection by suppressing JNK activation and inhibiting apoptotic cell death. Proteomics. 3, 513–526.CrossRefPubMedGoogle Scholar
  60. 60.
    Stankiewicz A.R., Lachapelle G., Foo C.P., Radicioni S.M., Mosser D.D. 2005. Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J. Biol. Chem. 280, 38729–38739.CrossRefPubMedGoogle Scholar
  61. 61.
    Garrido C., Galluzzi L., Brunet M., Puig P.E., Didelot C., Kroemer G. 2006. Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 13, 1423–1433.CrossRefPubMedGoogle Scholar
  62. 62.
    Mosser D.D., Caron A.W., Bourget L., Meriin A.B., Sherman M.Y., Morimoto R.I., Massie B. 2000. The chaperone function of Hsp70 is required for protection against stress-induced apoptosis. Mol. Cell. Biol. 20, 7146–7159.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Jaattela M., Wissing D., Kokholm K., Kallunki T., Egeblad M. 1998. HSP70 exerts its anti-apoptosic function downstream of caspase-3-like proteases. EMBO J. 17, 6124–6134.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Guzhova I.V., Margulis B.A. 2000. Induction and accumulation of HSP70 leads to formation of its complexes with other cell proteins. Tsitologiya. 42, 647–652.Google Scholar
  65. 65.
    Hargitai J., Lewis H., Boros I., Rácz T., Fiser A., Kurucz I., Benjamin I., Vígh L., Pénzes Z., Csermely P., Latchman D.S. 2003. Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1. Biochem. Biophys. Res. Commun. 307, 689‒695.CrossRefPubMedGoogle Scholar
  66. 66.
    Finka A., Sharma S.K., Goloubinoff P. 2015. Multi-layered molecular mechanisms of polypeptide holding, unfolding and disaggregation by HSP70/HSP110 chaperones. Front. Mol. Biosci. 2, article 29.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Gao X., Carroni M., Nussbaum-Krammer C., Mogk A., Nillegoda N.B., Szlachcic A., Guilbride D.L., Saibil H.R., Mayer M.P., Bukau B. 2015. Human Hsp70 disaggregase reverses Parkinson’s-linked α‑synuclein amyloid fibrils. Mol. Cell. 59, 781–793.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Jaattela M. 1999. Escaping cell death: Survival proteins in cancer. Exp. Cell Res. 248, 30‒43.CrossRefPubMedGoogle Scholar
  69. 69.
    Multhoff G., Hightower L.E. 2011. Distinguishing integral and receptor-bound heat shock protein 70 (Hsp70) on the cell surface by Hsp70-specific antibodies. Cell Stress Chaperones. 16, 251‒255.CrossRefPubMedGoogle Scholar
  70. 70.
    Zhai L.L., Xie Q., Zhou C.H., Huang D.W., Tang Z.G., Ju T.F. 2017. Overexpressed HSPA2 correlates with tumor angiogenesis and unfavorable prognosis in pancreatic carcinoma. Pancreatology. 17, 457‒463.CrossRefPubMedGoogle Scholar
  71. 71.
    Boudesco C., Cause S., Jego G., Garrido C. 2018. Hsp70: A cancer target inside and outside the cell. In: Chaperones: Methods and Protocols. Eds. Calderwood S.K., Prince T.L. Method in Molecular Biol. 1709, 371‒396.CrossRefGoogle Scholar
  72. 72.
    Hightower L.E., Guidon P.T., Jr. 1989. Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia–axon transfer proteins. J. Cell. Physiol. 138, 257–266.CrossRefPubMedGoogle Scholar
  73. 73.
    Pockley A.G., Shepherd J., Corton J.M. 1998. Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol. Invest. 27, 367–377.CrossRefPubMedGoogle Scholar
  74. 74.
    Clayton A., Turkes A., Navabi H., Mason M.D., Tabi Z. 2005. Induction of heat shock proteins in B-cell exosomes. J. Cell. Sci. 118, 3631–3638.CrossRefPubMedGoogle Scholar
  75. 75.
    Robinson M.B., Tidwell J.L., Gould T., Taylor A.R., Newbern J.M., Graves J., Tytell M., Milligan C.E. 2005. Extracellular heat shock protein 70: A critical component for motoneuron survival. J. Neurosci. 25, 9735–9745.CrossRefPubMedGoogle Scholar
  76. 76.
    Davies E.L., Bacelar M.M., Marshall M.J., Johnson E., Wardle T.D., Andrew S.M., Williams J.H. 2006. Heat shock proteins form part of a danger signal cascade in response to lipopolysaccharide and GroEL. Clin. Exp. Immunol. 145, 183–189.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Zhan R., Leng X., Liu X., Wang X., Gong J., Yan L., Wang L., Wang Y., Wang X., Qian L.J. 2009. Heat shock protein 70 is secreted from endothelial cells by a non-classical pathway involving exosomes. Biochem. Biophys. Res. Commun. 387, 229–233.CrossRefPubMedGoogle Scholar
  78. 78.
    Beckett K., Monier S., Palmer L., Alexandre C., Green H., Bonneil E., Raposo G., Thibault P., Le Borgne R., Vincent J.P. 2013. Drosophila S2 cells secrete wingless on exosome-like vesicles but the wingless gradient forms independently of exosomes. Traffic. 14, 82–96.CrossRefPubMedGoogle Scholar
  79. 79.
    Takeuchi T., Suzuki M., Fujikake N., Popiel H.A., Kikuchi H., Futaki S., Wada K., Nagai Y. 2015. Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level. Proc. Natl. Acad. Sci. U. S. A. 112, E2497‒E2506.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Mambula S.S., Calderwood S.K. 2006. Heat shock protein 70 is secreted from tumor cells by nonclassical pathway involving lysosomal endosomes. J. Immunol. 177, 7849–7857.CrossRefPubMedGoogle Scholar
  81. 81.
    Mambula S.S., Stevenson M.A., Ogawa K., Calderwood S.K. 2007. Mechanisms for Hsp70 secretion: Crossing membranes without a leader. Methods. 43, 168–175.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Prudovsky I., Mandinova A., Soldi R., Bagala C., Graziani I., Landriscina M., Tarantini F., Duarte M., Bellum S., Doherty H., Maciag T. 2003. The non-classical export routes: FGF1 and IL-1alpha point the way. J. Cell. Sci. 116, 4871–4881.CrossRefPubMedGoogle Scholar
  83. 83.
    Ferrari D., Pizzirani C., Adinolfi E., Lemoli R.M., Curti A., Idzko M., Panther E., Di Virgilio F. 2006. The P2X7 receptor: A key player in IL-1 processing and release. J. Immunol. 176, 3877–3883.CrossRefPubMedGoogle Scholar
  84. 84.
    Arispe N., Doh M., Simakova O., Kurganov B., De Maio A. 2004. Hsc70 and Hsp70 interact with phosphatidylserine on the surface of PC12 cells resulting in a decrease of viability. FASEB J. 18, 1636–1645.CrossRefPubMedGoogle Scholar
  85. 85.
    Schilling D., Gehrmann M., Steinem C., De Maio A., Pockley A.G., Abend M., Molls M., Multhoff G. 2009. Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells. FASEB J. 23, 2467–2477.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Asea A. 2007. Mechanisms of HSP72 release. J. Biosci. 32, 579–584.CrossRefPubMedGoogle Scholar
  87. 87.
    Vega V.L., Rodríguez-Silva M., Frey T., Gehrmann M., Diaz J.C., Steinem C., Multhoff G., Arispe N., De Maio A. 2008. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J. Immunol. 180, 4299–4307.CrossRefPubMedGoogle Scholar
  88. 88.
    Tsai T.N., Lee T.Y., Liu M.S., Chuang I.C., Lu M.C., Dong H.P., Lue S.I., Yang R.C. 2015. Release of endogenous heat shock protein 72 on the survival of sepsis in rats. J. Surg. Res. 198, 165–174.CrossRefPubMedGoogle Scholar
  89. 89.
    Macleod C., Bryant C.E. 2017. Visualising pattern recognition receptor signalling. Biochem. Soc. Trans. 45, 1077‒1085.CrossRefPubMedGoogle Scholar
  90. 90.
    Basu S., Binder R.J., Ramalingam T., Srivastava P.K. 2001. CD91 is a common receptor for heat shock proteins gp96, Hsp90, Hsp70, and calreticulin. Immunity. 14, 303–313.CrossRefPubMedGoogle Scholar
  91. 91.
    Takemoto S., Nishikawa M., Takakura Y. 2005. Pharmacokinetic and tissue distribution mechanism of mouse recombinant heat shock protein 70 in mice. Pharm. Res. 22, 419‒426.CrossRefPubMedGoogle Scholar
  92. 92.
    Wang Y., Kelly C.G., Karttunen J.T., Whittall T., Lehner P.J., Duncan L., MacAry P., Younson J.S., Singh M., Oehlmann W., Cheng G., Bergmeier L., Lehner T. 2001. CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity. 15, 971–983.CrossRefPubMedGoogle Scholar
  93. 93.
    Asea A. 2008. Hsp70: A chaperokine. Novartis Found. Symp. 291, 173–179.CrossRefPubMedGoogle Scholar
  94. 94.
    Srivastava P. 2002. Interaction of heat shock proteins with peptides and antigen presenting cells: Chaperoning of the innate and adaptive immune responses. Annu. Rev. Immunol. 20, 395–425.CrossRefPubMedGoogle Scholar
  95. 95.
    Asea A., Kraeft S.K., Kurt-Jones E.A., Stevenson M.A., Chen L.B., Finberg R.W., Koo G.C., Calderwood S.K. 2000. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat. Med. 6, 435–442.Google Scholar
  96. 96.
    Fleshner M., Johnson J.D. 2005. Endogenous extra-cellular heat shock protein 72: Releasing signal(s) and function. Int. J. Hyperthermia. 21, 457–471.CrossRefPubMedGoogle Scholar
  97. 97.
    Lee K.H., Jeong J., Yoo C.G. 2013. Positive feedback regulation of heat shock protein 70 (Hsp70) is mediated through Toll-like receptor 4-PI3K/Akt-glycogen synthase kinase-3β pathway. Exp. Cell Res. 319, 88–95.CrossRefPubMedGoogle Scholar
  98. 98.
    Ko R., Lee S.Y. 2016. Glycogen synthase kinase 3β in Toll-like receptor signaling. BMB Rep. 49, 305–310.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Bausinger H., Lipsker D., Ziylan U., Manié S., Briand J.P., Cazenave J.P., Muller S., Haeuw J.F., Ravanat C., de la Salle H., Hanau D. 2002. Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur. J. Immunol. 32, 3708–3713.CrossRefPubMedGoogle Scholar
  100. 100.
    Gao B., Tsan M. F. 2003. Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70) preparation is responsible for the induction of tumor necrosis factor alpha release by murine macrophages. J. Biol. Chem. 278, 174‒179.CrossRefPubMedGoogle Scholar
  101. 101.
    Rozhkova E., Yurinskaya M., Zatsepina O., Garbuz D., Karpov V., Surkov S., Murashev A., Ostrov V., Margulis B., Evgen’ev M., Vinokurov M. 2010. Exogenous mammalian extracellular HSP70 reduces endotoxin manifestations at the cellular and organism levels. Ann. N.Y. Acad. Sci. 1197, 94–107.CrossRefPubMedGoogle Scholar
  102. 102.
    Aneja R., Odoms K., Dunsmore K., Shanley T.P., Wong H.R. 2006. Extracellular heat shock protein-70 induces endotoxin tolerance in THP-1 cells. J. Immunol. 177, 7184–7192.CrossRefPubMedGoogle Scholar
  103. 103.
    Borges T.J., Lopes R.L., Pinho N.G., Machado F.D., Souza A.P., Bonorino C. 2013. Extracellular Hsp70 inhibits pro-inflammatory cytokine production by IL-10 driven down-regulation of C/EBPβ and C/EBPδ. Int. J. Hyperthermia. 29, 455–463.CrossRefPubMedGoogle Scholar
  104. 104.
    Hsu J.H., Yang R.C., Lin S.J., Liou S.F., Dai Z.K., Yeh J.L., Wu J.R. 2014. Exogenous heat shock cognate protein 70 pretreatment attenuates cardiac and hepatic dysfunction with associated anti-inflammatory responses in experimental septic shock. Shock. 42, 540–547.CrossRefPubMedGoogle Scholar
  105. 105.
    Troyanova N.I., Shevchenko M.A., Boiko A.A., Mirzoev R.R., Pertseva M.A., Kovalenko E.I., Sapozhnikov A.M. 2015. Modulating effect of extracellular HSP70 on generation of reactive oxigen speciesin populations of phagocytes. Russ. J. Bioorg. Chem. 41 (3), 271‒279.CrossRefGoogle Scholar
  106. 106.
    Shevchenko M.A., Troyanova N.I., Servuli E.A., Bolkhovitina E.L., Fedorina A.S., Sapozhnikov A.M. 2016. Study of immunomodulatory effects of extracellular HSP70 in a mouse model of allergic airway inflammation. Biochemistry (Moscow). 81 (11), 1384–1395.PubMedGoogle Scholar
  107. 107.
    Yurinskaya M., Zatsepina O.G., Vinokurov M.G., Bobkova N.V., Garbuz D.G., Morozov A.V., Kulikova D.A., Mitkevich V.A., Makarov A.A., Funikov S.Y., Evgen’ev M.B. 2015. The fate of exogenous human HSP70 introduced into animal cells by different means. Curr. Drug Deliv. 12, 524–532.CrossRefPubMedGoogle Scholar
  108. 108.
    Peri F., Calabrese V. 2014. Toll-like receptor 4 (TLR4) modulation by synthetic and natural compounds: an update. J. Med. Chem. 57, 3612–3622.CrossRefPubMedGoogle Scholar
  109. 109.
    Ofengeim D., Yuan J. 2013. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14, 727–736.CrossRefGoogle Scholar
  110. 110.
    Angus D.C., Wax R.S. 2001. Epidemiology of sepsis: An update. Crit. Care Med. 29, S109–S116.CrossRefPubMedGoogle Scholar
  111. 111.
    van Zanten A.R., Brinkman S., Arbous M.S., Abu-Hanna A., Levy M.M., de Keizer N.F.; Netherlands Patient Safety Agency Sepsis Expert Group. 2014. Guideline bundles adherence and mortality in severe sepsis and septic shock. Crit. Care Med. 42, 1890‒1898.CrossRefPubMedGoogle Scholar
  112. 112.
    Zhang Y.H., Takahashi K., Jiang G.Z., Zhang X.M., Kawai M., Fukada M., Yokochi T. 1994. In vivo production of heat shock protein in mouse peritoneal macrophages by administration of lipopolysaccharide. Infect. Immun. 62, 4140–4144.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Gupta A., Cooper Z.A., Tulapurkar M.E., Potla R., Maity T., Hasday J.D., Singh I.S. 2013. Toll-like receptor agonists and febrile range hyperthermia synergize to induce heat shock protein 70 expression and extracellular release. J. Biol. Chem. 288, 2756‒2766.CrossRefPubMedGoogle Scholar
  114. 114.
    Wheeler D.S., Fisher L.E., Jr., Catravas J.D., Jacobs B.R., Carcillo J.A., Wong H.R. 2005. Extracellular hsp70 levels in children with septic shock. Pediatr. Crit. Care Med. 6, 308–311.CrossRefPubMedGoogle Scholar
  115. 115.
    Nakada J., Matsura T., Okazaki N., Nishida T., Togawa A., Minami Y., Inagaki Y., Ito H., Yamada K., Ishibe Y. 2005. Oral administration of geranylgeranylacetone improves survival rate in a rat endotoxin shock model: Administration timing and heat shock protein 70 induction. Shock. 24, 482–487.CrossRefPubMedGoogle Scholar
  116. 116.
    Kustanova G., Murashev A., Karpov V.L., Margulis B.A., Guzhova I.V., Prokhorenko I.R., Grachev S.V., Evgen’ev M.B. 2006. Exogenous heat shock protein 70 mediates sepsis manifestations and decreases the mortality rate in rats. Cell Stress Chaperones. 11, 276–286.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Vinokurov M., Ostrov V., Yurinskaya M., Garbuz D., Murashev A., Antonova O., Evgen’ev M. 2012. Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels. Cell Stress Chaperones. 17, 89–101.CrossRefPubMedGoogle Scholar
  118. 118.
    Yurinskaya M.M., Vinokurov M.G., Zatsepina O.G., Garbuz D.G., Guzhova I.V., Rozhkova E.A., Suslikov A.V., Karpov V.L., Evgen’ev M.B. 2009. Exogenous heat shock proteins HSP70 suppress endotoxin-induced activation of human neutrophils. Dokl. Akad. Nauk. 426, 406–409.Google Scholar
  119. 119.
    Ostrov V.F., Slashcheva G.A., Zharmukhamedova T.Yu., Garbuz D.G., Evgen’ev M.B., Murashev A.N. 2010. The Influence of the recombinant human heat shock protein Hsp70 in the biochemical properties of blood during endotoxic shock simulation in rats. Russ. J. Bioorg. Chem. 36 (3), 310–314.CrossRefGoogle Scholar
  120. 120.
    Shin H.J., Lee H., Park J.D., Hyun H.C., Sohn H.O., Lee D.W., Kim Y.S. 2007. Kinetics of binding of LPS to recombinant CD14, TLR4, and MD-2 proteins. Mol. Cells. 24, 119–124.PubMedGoogle Scholar
  121. 121.
    Afrazi A., Sodhi C.P., Good M., Jia H., Siggers R., Yazji I., Ma C., Neal M.D., Prindle T., Grant Z.S., Branca M.F., Ozolek J., Chang E.B., Hackam D.J. 2012. Intracellular heat shock protein-70 negatively regulates TLR4 signaling in the newborn intestinal epithelium. J. Immunol. 188, 4543–4557.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Multhoff G., Botzler C., Wiesnet M., Müller E., Meier T., Wilmanns W., Issels R.D. 1995. A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int. J. Cancer. 61, 272‒279.CrossRefPubMedGoogle Scholar
  123. 123.
    Multhoff G., Botzler C., Jennen L., Schmidt J., Ellwart J., Issels R. 1997. Heat shock protein 72 on tumor cells: A recognition structure for natural killer cells. J. Immunol. 158, 4341‒4350.PubMedGoogle Scholar
  124. 124.
    Jun Ho Jang, Hanash S. 2003. Profiling of the cell surface proteome. Proteomics. 3, 1947–1954.Google Scholar
  125. 125.
    Roigas J., Wallen E.S., Loening S.A., Moseley P.L. 1998. Heat shock protein (HSP72) surface expression enhances the lysis of a human renal cell carcinoma by IL-2 stimulated NK cells. Adv. Exp. Med. Biol. 451, 225‒229.CrossRefPubMedGoogle Scholar
  126. 126.
    Ponomarev E.D., Tarasenko T.N., Sapozhnikov A.M. 2000. Splenic cytotoxic cells recognize surface HSP70 on culture-adapted EL-4 mouse lymphoma cells. Immunol. Lett. 74, 133‒139.CrossRefPubMedGoogle Scholar
  127. 127.
    Bausero M.A., Gastpar R., Multhoff G., Asea A. 2005. Alternative mechanism by which IFN-gamma enhances tumor recognition: Active release of heat shock protein 72. J. Immunol. 175, 2900‒2912.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Chalmin F., Ladoire S., Mignot G., Vincent J., Bruchard M., Remy-Martin J.P., Boireau W., Rouleau A., Simon B., Lanneau D., De Thonel A., Multhoff G., Hamman A., Martin F., Chauffert B., et al. 2010. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J. Clin. Invest. 120, 457–471.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Rérole A.L., Gobbo J., De Thonel A., Schmitt E., Pais de Barros J.P., Hammann A., Lanneau D., Fourmaux E., Demidov O.N., Micheau O., Lagrost L., Colas P., Kroemer G., Garrido C. 2011. Peptides and aptamers targeting HSP70: A novel approach for anticancer chemotherapy. Cancer Res. 71, 484–495.CrossRefPubMedGoogle Scholar
  130. 130.
    Zihai Li. 2003. Role of heat shock protein in chaperoning tumor antigens and modulating anti-tumor immunity. In: Tumor Antigens Recognized by T Cells and Antibodies. Eds. Hans J. Stauss, Kawakami Y., Parmiani G. New York: Taylor and Francis, pp. 20–33Google Scholar
  131. 131.
    Shevtsov M., Multhoff G. 2016. Heat shock protein-peptide and HSP-based immunotherapies for the treatment of cancer. Front. Immunol. 7, article 171.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Galvin J.E., Howard D.H., Denny S.S., Dickinson S., Tatton N. 2017. The social and economic burden of frontotemporal degeneration. Neurology. 89, 2049–2056.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Marešová P., Dolejš J., Kuca K. 2018. Call for a uniform strategy of collecting Alzheimer’s disease costs: A review and meta-analysis. J. Alzheimers Dis. 63, 227–238.CrossRefPubMedGoogle Scholar
  134. 134.
    Reisberg B., Saeed M.U. 2004. Alzheimer’s disease. In: Comprehensive Textbook of Geriatric Psychiatry, 3rd ed. Eds. Sadavoy J., Jarvik L.F., Grossberg G.T., Meyers B.S. New York: W.W. Norton, pp. 449–509Google Scholar
  135. 135.
    Clayton K.A., Van Enoo A.A., Ikezu T. 2017. Alzheimer’s disease: The role of microglia in brain homeostasis and proteopathy. Front. Neurosci. 11, article 680.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Schwarzman A.L., Sarantseva S.V. 2017. Transmission of pathogenic protein aggregates in Alzheimer’s disease. Mol. Biol. (Moscow). 51 (3), 368–371.CrossRefGoogle Scholar
  137. 137.
    Grimm A., Friedland K., Eckert A. 2016. Mitochondrial dysfunction: The missing link between aging and sporadic Alzheimer’s disease. Biogerontology. 17, 281‒296.CrossRefPubMedGoogle Scholar
  138. 138.
    Ahmad K., Baig M.H., Mushtaq G., Kamal M.A., Greig N.H., Choi I. 2017. Commonalities in biological pathways, genetics, and cellular mechanism between Alzheimer disease and other neurodegenerative diseases: An in silico-updated overview. Curr. Alzheimer Res. 14, 1190‒1197.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Yang G., Wang Y., Tian J., Liu J.P. 2013. Huperzine A for Alzheimer’s disease: A systematic review and meta-analysis of randomized clinical trials. PLoS One. 8, e74916.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Ehret M.J., Chamberlin K.W. 2015. Current practices in the treatment of Alzheimer disease: Where is the evidence after the Phase III trials? Clin. Ther. 37, 1604‒1616.CrossRefPubMedGoogle Scholar
  141. 141.
    Tatarnikova O.G., Orlov M.A., Bobkova N.V. 2015. Beta-amyloid and Tau protein: Structure, properties, and prion-like properties. Usp. Biol. Khim. 55, 351–390.Google Scholar
  142. 142.
    Kumar D., Ganeshpurkar A., Kumar D., Modi G., Gupta S.K., Singh S.K. 2018. Secretase inhibitors for the treatment of Alzheimer’s disease: Long road ahead. Eur. J. Med. Chem. 148, 436–452.CrossRefPubMedGoogle Scholar
  143. 143.
    Franklin T.B., Krueger-Naug A.M., Clarke D.B., Arrigo A.P., Currie R.W. 2005. The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. Int. J. Hyperthermia. 21, 379–392.CrossRefPubMedGoogle Scholar
  144. 144.
    Leak R.K. 2014. Heat shock proteins in neurodegenerative disorders and aging. J. Cell Commun. Signal. 8, 293–310.CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Sulistio Y.A., Heese K. 2016. The ubiquitin-proteasome system and molecular chaperone deregulation in Alzheimer’s disease. Mol. Neurobiol. 53, 905–931.CrossRefPubMedGoogle Scholar
  146. 146.
    Sun Y., Zhang J.R., Chen S. 2017. Suppression of Alzheimer’s disease-related phenotypes by the heat shock protein 70 inducer, geranylgeranylacetone, in APP/PS1 transgenic mice via the ERK/p38 MAPK signaling pathway. Exp. Ther. Med. 14, 5267‒5274.PubMedPubMedCentralGoogle Scholar
  147. 147.
    Dursun E., Gezen-Ak D., Hanağası H., Bilgiç B., Lohmann E., Ertan S., Atasoy İ.L., Alaylıoğlu M., Araz Ö.S., Önal B., Gündüz A., Apaydın H., Kızıltan G., Ulutin T., Gürvit H., Yılmazer S. 2015. The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer’s disease, mild cognitive impairment or Parkinson’s disease. J. Neuroimmunol. 283, 50–57.CrossRefPubMedGoogle Scholar
  148. 148.
    Taipa R., Sousa A.L., Melo Pires M., Sousa N. 2016. Does the interplay between aging and neuroinflammation modulate Alzheimer’s disease clinical phenotypes? A clinico-pathological perspective. J. Alzheimers Dis. 53, 403–417.CrossRefPubMedGoogle Scholar
  149. 149.
    Pugazhenthi S., Qin L., Reddy P.H. 2017. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim. Biophys. Acta. 1863, 1037‒1045.CrossRefGoogle Scholar
  150. 150.
    Heppner F.L., Ransohoff R.M., Becher B. 2015. Immune attack: The role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372.CrossRefPubMedGoogle Scholar
  151. 151.
    Zhang F., Jiang L. 2015. Neuroinflammation in Alzheimer’s disease. Neuropsychiatr. Dis. Treat. 11, 243–256.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Heneka M.T., Carson M.J., Khoury J.E., Landreth G.E., Brosseron F., Feinstein D.L., Jacobs A.H., Wyss-Coray T., Vitorica J., Ransohoff R.M., Herrup K., Frautschy S.A., Finsen B, Brown G.C., Verkhratsky A., et al. 2015. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405.CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Bolós M., Perea J.R., Avila J. 2017. Alzheimer’s disease as an inflammatory disease. Biomol. Concepts. 8, 37–43.CrossRefPubMedGoogle Scholar
  154. 154.
    Nazem A., Sankowski R., Bacher M., Al-Abed Y. 2015. Rodent models of neuroinflammation for Alzheimer’s disease. J. Neuroinflammation. 12, 74.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Balistreri C.R., Grimaldi M.P., Chiappelli M., Licastro F., Castiglia L., Listì F., Vasto S., Lio D., Caruso C., Candore G. 2008. Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer’s disease. Curr. Pharm. Des. 14, 2672–2677.CrossRefPubMedGoogle Scholar
  156. 156.
    Chen Y., Yip P., Huang Y., Sun Y., Wen L.L., Chu Y.M., Chen T.F. 2012. Sequence variants of Toll Like receptor 4 and late-onset Alzheimer’s disease. PLoS One. 7, e50771.CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Tahara K., Kim H.D., Jin J.J., Maxwell J.A., Li L., Fukuchi K. 2006. Role of Toll-like receptor signalling in Aβ uptake and clearance. Brain. 129, 3006–3019.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Jin J.J., Kim H.D., Maxwell J.A., Li L., Fukuchi K. 2008. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J. Neuroinflammation. 5, 23.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Tang S.C., Lathia J.D., Selvaraj P.K., Jo D.G., Mughala M.R., Cheng A., Siler D.A., Markesbery W.R., Arumugam T.V., Mattson M.P. 2008. Toll-Like receptor-4 mediates neuronal apoptosis induced by amyloid β-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp. Neurol. 213, 114–121.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Meriin A.B., Sherman M.Y. 2005. Role of molecular chaperones in neurodegenerative disorders. Int. J. Hyperthermia. 21, 403–419.CrossRefPubMedGoogle Scholar
  161. 161.
    Ekimova I.V., Nitsinskaya L.E., Romanova I.V., Pastukhov Y.F., Margulis B.A., Guzhova I.V. 2010. Exogenous protein Hsp70/Hsc70 can penetrate into brain structures and attenuate the severity of chemically-induced seizures. J. Neurochem. 115, 1035–1044.CrossRefPubMedGoogle Scholar
  162. 162.
    Magrané J., Smith R.C., Walsh K., Querfurth H.W. 2004. Heat shock protein 70 participates in the neuroprotective response to intracellularly expressed beta-amyloid in neurons. J. Neurosci. 24, 1700–1706.CrossRefPubMedGoogle Scholar
  163. 163.
    Calabrese V., Stella A.M., Butterfield D.A., Scapagnini G. 2004. Redox regulation in neurodegeneration and longevity: Role of the heme oxygenase and HSP70 systems in brain stress tolerance. Antioxid. Redox Signal. 6, 895‒913.PubMedGoogle Scholar
  164. 164.
    Lu R., Tan M., Wang H., Xie A.M., Yu J.T., Tan L. 2014. Heat Shock Protein 70 in Alzheimer’s disease. Biomed. Res. Int. 2014, 435203.PubMedPubMedCentralGoogle Scholar
  165. 165.
    Lazarev V.F., Mikhaylova E.R., Guzhova I.V., Margulis B.A. 2017. Possible function of molecular chaperones in diseases caused by propagating amyloid aggregates. Front. Neurosci. 11, 277.CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Rivera I., Capone R., Cauvi D.M., Arispe N., De Maio A. 2018. Modulation of Alzheimer’s amyloid β peptide oligomerization and toxicity by extracellular Hsp70. Cell Stress Chaperones. 23, 269–279.CrossRefPubMedGoogle Scholar
  167. 167.
    Bobkova N.V., Nesterova I.V., Medvinskaya N.I., Aleksandrova I.Y., Samokhin A.N., Gershovich Y.G., Gershovich P.M., Yashin V.A. 2005. Possible role of olfactory system in Alzheimer’s disease genesis. In: New Trends in Alzheimer and Parkinson Related Disorders: ADPD 2005. Eds. Fisher A., Hanin L., Memo M., F. Stocchi. Medimond, pp. 91–95.Google Scholar
  168. 168.
    Holland D., Brewer J.B., Hagler D.J., Fennema-Notestine C., Dale A.D., and the Alzheimer’s Disease Neuroimaging Initiative. 2009. Subregional neuroanatomical change as a biomarker for Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 106, 20954–20959.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Oakley H., Cole S.L., Logan S., Maus E., Shao P., Craft J., Guillozet-Bongaarts A., Ohno M., Disterhoft J., Van Eldik L., Berry R., Vassar R. 2006. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140.CrossRefPubMedGoogle Scholar
  170. 170.
    Jogani V., Jinturkar K., Vyas T., Misra A. 2008. Recent patents review on intranasal administration for CNS drug delivery. Recent Pat. Drug. Deliv. Formul. 2, 25–40.CrossRefPubMedGoogle Scholar
  171. 171.
    Ying W. 2008. The nose may help the brain: Intranasal drug delivery for treating neurological diseases. Future Neurol. 3, 1–4.CrossRefGoogle Scholar
  172. 172.
    Falcone J.A., Salameh T.S., Yi X., Cordy B.J., Mortell W.G., Kabanov A.V., Banks W.A. 2014. Intranasal administration as a route for drug delivery to the brain: Evidence for a unique pathway for albumin. J. Pharmacol. Exp. Ther. 351, 54–60.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Black S.A., Stys P.K., Zamponi G.W., Tsutsui S. 2014. Cellular prion protein and NMDA receptor modulation: Protecting against excitotoxicity. Front. Cell. Dev. Biol. 2, 45.CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Rebeck G.W., Reiter J.S., Strickland D.K., Hyman B.T. 1993. Apolipoprotein E in sporadic Alzheimer’s disease: Allelic variation and receptor interactions. Neuron. 11, 575–580.CrossRefPubMedGoogle Scholar
  175. 175.
    Xiao H., Gao Y., Liu L., Li Y. 2017. Association between polymorphisms in the promoter region of the apolipoprotein E (APOE) gene and Alzheimer’s disease: A meta-analysis. EXCLI J. 16, 921–938.PubMedPubMedCentralGoogle Scholar
  176. 176.
    Strickland D.K., Kounnas M.Z., Argraves W.S. 1995. LDL receptor-related protein: A multiligand receptor for lipoprotein and proteinase catabolism. FASEB J. 9, 890–898.CrossRefPubMedGoogle Scholar
  177. 177.
    Bobkova N., Guzhova I., Margulis B., Nesterova I., Medvinskaya N., Samokhin A., Alexandrova I., Garbuz D., Nudler E., Evgen’ev M. 2013. Dynamics of endogenous Hsp70 synthesis in the brain of olfactory bulbectomized mice. Cell Stress Chaperones. 18, 109–118.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  • D. G. Garbuz
    • 1
    Email author
  • O. G. Zatsepina
    • 1
  • M. B. Evgen’ev
    • 1
  1. 1.Engelhardt Institute of Molecular Biology, Russian Academy of SciencesMoscowRussia

Personalised recommendations