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Role of interaction of beta-amyloid and Tau-protein in pathogenesis of Alzheimer’s disease

Keywords:

N. V. Bobkova – Ph.D. (Biol.), Head of the Laboratory, ICB RAS (Pushchino, Moscow Region). E-mail: nbobkova@mail.ru
O. G. Tatarnikova – Master's Student, Moscow State University n.a. M.V. Lomonosov Engineer, ICB RAS (Pushchino, Moscow Region). E-mail: olga.psn@mail.ru
A. N. Klenyaeva – Post-graduate Student, ICB RAS (Pushchino, Moscow Region). E-mail: a-lina-a@yandex.ru
M. A. Orlov – Master's Student, Moscow State University n.a. M.V. Lomonosov. E-mail: fire-vortex@mail.ru
M. M. Panchenko – Post-graduate Student, ICB RAS (Pushchino, Moscow Region). E-mail: mmpanchenko@gmail.com
S. V. Leonov – Senior Research Scientist, ICB RAS (Pushchino, Moscow Region)


Extracellular amyloid plaques comprising Аβ and intracellular neurofibrillary tangles, primarily composed of coupled protein Tau filaments are the major morphological markers of Alzheimer's disease (AD). Study of the functional role of these proteins separated researchers at two «camps» in accordance with the accepted hypothesis of the pathogenesis of AD «amyloid cascade hypothesis», insisting on a key role of Аβ [1], and «tau-hypothesis», giving priority to Tau protein [2]. The idea about the interaction between Аβ and Tau protein for a long time was not finding support. Recently, it was shown the possibility of physicochemical interaction Аβ and Tau protein, leading to the formation of soluble complex that through the activation of GSK3beta enhances phosphorylation of Tau and induces its aggregation [3]. It is assumed that the oligomers of Аβ can induce toxic forms of Tau protein in neurons [4], which leads to the collapse of the transport system, disruption of synaptic apparatus, and cell death [5]. At the same time the possibility of penetration of Tau protein oligomers and βA through the mechanism of endocytosis into healthy neurons and induction of aggregation of own «healthy» Tau protein have been revealed [6]. This process can lead to the selective and directed spreading similar to infection oligomeric forms of proteins between the target cells [7]. Opening prion-like activity in oligomeric forms of Аβ and Tau protein causes a new view on pathogenesis of AD [8]. Using cell cultures opens up new possibilities in the study of the mechanisms of direct influence Аβ and Tau protein on the survival of neurons. We have developed the cell model, allowing to investigate separate and combined effects of secreted oligomeric forms of Аβ and Tau protein, as well as to test the effects of new drugs with protective function. Our results demonstrate the leading role of Tau protein in mediating the toxic effect of Aβ that apparently occurs for AD. The creation of such high-tech cellular models suitable for screening of pharmacological agents to prevent the formation of toxic forms of Tau and Аβ is currently one of the newest and most promising areas of drug development against AD, in what is needs so much modern medicine. The study was supported by Program of PRAN 2014.
References:

  1. Hardy J., Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease // Trends Pharmacol Sci. 1991. V. 12. P. 383–388.
  2. Trojanowski J.Q., Lee V.M. The role of tau in Alzheimer's disease. Med Clin North Am. 2002. V. 86(3). P. 615-27.
  3. Nussbaum J.M., Seward M.E. and Bloom G.S. Alzheimer disease. A tale of two prions //Prion. 2013. V. 7(1). P. 14-19.
  4. Lasagna-Reeves C.A., Castillo-Carranza D.L., Guerrero-Muoz M.J., Jackson G.R., Kayed R. Preparation and characterization of neurotoxic tau oligomers. Biochemistry. 2010. V. 49(47). P. 10039-10041.
  5. Guo J.L., Lee V.M. Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau // FEBS Lett. 2013. V. 587(6). P. 717-723.
  6. Duyckaerts C. Neurodegenerative lesions. Seeding and spreading // Rev Neurol (Paris). 2013. V. 169(10). P. 825-833.
  7. Hanger D.P., et al.Intracellular and Extracellular Roles for Tau in Neurodegenerative Disease // J. Alzheimers Dis. 2014.
  8. Kfoury N., Holmes B.B., Jiang H., Holtzman D.M., Diamond M.I. Trans-cellular propagation of tau aggregation by fibrillar species //J. Biol. Chem. 2012. 287. 19440–51; Kfoury et al., 2012. 

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