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

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Abstract

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.

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REFERENCES

  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.

    Article  CAS  PubMed  Google Scholar 

  2. Mayer M.P. 2010. Gymnastics of molecular chaperones. Mol. Cell. 39, 321–331.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  5. Barua D., Heckathorn S.A. 2004. Acclimation of the temperature set-points of the heat-shock response. J. Therm. Biol. 29, 185–193.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Book  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  10. Hartl F.U., Bracher A., Hayer-Hartl M. 2011. Molecular chaperones in protein folding and proteostasis. Nature. 475, 324–332.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Milner C.M., Campbell R.D. 1990. Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics. 32, 242–251.

    Article  CAS  PubMed  Google Scholar 

  21. Milner C.M., Campbell R.D. 1992. Polymorphic analysis of three MHC-linked HSP70 genes. Immunogenetics. 36, 357–362.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  26. Flajnik M.F., Canel C., Kramer J., Kasahara M. 1991. Which came first, MHC class I or class II? Immunogenetics. 33, 295–300.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  29. Guzhova I., Margulis B. 2006. Hsp70 chaperone as a survival factor in cell pathology. Int. Rev. Cytol. 254, 101‒149.

    Article  CAS  PubMed  Google Scholar 

  30. Frydman J. 2001. Folding of newly translated proteins in vivo: The role of molecular chaperones. Annu. Rev. Biochem. 70, 603–647.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  37. Arias E., Cuervo A.M. 2011. Chaperone-mediated autophagy in protein quality control. Curr. Opin. Cell Biol. 23, 184–189.

    Article  CAS  PubMed  Google Scholar 

  38. Fan A.C., Young J.C. 2011. Function of cytosolic chaperones in Tom70-mediated mitochondrial import. Protein Pept. Lett. 18, 122‒131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sousa R., Lafer E.M. 2006. Keep the traffic moving: mechanism of the Hsp70 motor. Traffic. 7, 1596‒1603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  44. Melnick J., Argon Y. 1995. Molecular chaperones and the biosynthesis of antigen receptors. Immunol. Today. 16, 243–250.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jaattela M. 1999. Escaping cell death: Survival proteins in cancer. Exp. Cell Res. 248, 30‒43.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Asea A. 2007. Mechanisms of HSP72 release. J. Biosci. 32, 579–584.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  89. Macleod C., Bryant C.E. 2017. Visualising pattern recognition receptor signalling. Biochem. Soc. Trans. 45, 1077‒1085.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  93. Asea A. 2008. Hsp70: A chaperokine. Novartis Found. Symp. 291, 173–179.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  98. Ko R., Lee S.Y. 2016. Glycogen synthase kinase 3β in Toll-like receptor signaling. BMB Rep. 49, 305–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  110. Angus D.C., Wax R.S. 2001. Epidemiology of sepsis: An update. Crit. Care Med. 29, S109–S116.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  124. Jun Ho Jang, Hanash S. 2003. Profiling of the cell surface proteome. Proteomics. 3, 1947–1954.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 20–33

  131. Shevtsov M., Multhoff G. 2016. Heat shock protein-peptide and HSP-based immunotherapies for the treatment of cancer. Front. Immunol. 7, article 171.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 449–509

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Schwarzman A.L., Sarantseva S.V. 2017. Transmission of pathogenic protein aggregates in Alzheimer’s disease. Mol. Biol. (Moscow). 51 (3), 368–371.

    Article  CAS  Google Scholar 

  137. Grimm A., Friedland K., Eckert A. 2016. Mitochondrial dysfunction: The missing link between aging and sporadic Alzheimer’s disease. Biogerontology. 17, 281‒296.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  144. Leak R.K. 2014. Heat shock proteins in neurodegenerative disorders and aging. J. Cell Commun. Signal. 8, 293–310.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Sulistio Y.A., Heese K. 2016. The ubiquitin-proteasome system and molecular chaperone deregulation in Alzheimer’s disease. Mol. Neurobiol. 53, 905–931.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  151. Zhang F., Jiang L. 2015. Neuroinflammation in Alzheimer’s disease. Neuropsychiatr. Dis. Treat. 11, 243–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Bolós M., Perea J.R., Avila J. 2017. Alzheimer’s disease as an inflammatory disease. Biomol. Concepts. 8, 37–43.

    Article  CAS  PubMed  Google Scholar 

  154. Nazem A., Sankowski R., Bacher M., Al-Abed Y. 2015. Rodent models of neuroinflammation for Alzheimer’s disease. J. Neuroinflammation. 12, 74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Meriin A.B., Sherman M.Y. 2005. Role of molecular chaperones in neurodegenerative disorders. Int. J. Hyperthermia. 21, 403–419.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  171. Ying W. 2008. The nose may help the brain: Intranasal drug delivery for treating neurological diseases. Future Neurol. 3, 1–4.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to D. G. Garbuz.

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Translated by T. Tkacheva

Abbreviations: ROS, reactive oxygen species; LPS, lipopolysaccharide; APP, amyloid precursor protein; eHsp70, exogenous Hsp70; Hsp, heat shock protein; TLR, Toll-like receptor; AD, Alzheimer’s disease; HS, heat shock.

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Garbuz, D.G., Zatsepina, O.G. & Evgen’ev, M.B. The Major Human Stress Protein Hsp70 as a Factor of Protein Homeostasis and a Cytokine-Like Regulator. Mol Biol 53, 176–191 (2019). https://doi.org/10.1134/S0026893319020055

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