FEATURES OF EXPRESSION OF β-AMYLOID IN CEREBRAL ENDOTHELIAL CELLS IN EXPERIMENTAL ALZHEIMER’S DISEASE

DOI: https://doi.org/10.29296/24999490-2021-02-04

Ya.V. Gorina, E.D. Osipova, A.V. Morgun, O.L. Lopatina, E.V. Kharitonova, A.B. Salmina Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Partizana Zheleznyaka str., 1, Krasnoyarsk, 660022, Russian Federation E-mail: yana_20@bk.ru

Introduction. The formation of neurofibrillary plexuses and the accumulation of senile plaques in the parenchyma and cerebral vessels are the key pathological signs of Alzheimer’s disease presenting a neurodegenerative disease. The main component of senile plaques is β-amyloid. The aim of the study. To study the expression of β-amyloid in cells of cerebral endothelium of the hippocampus in experimental Alzheimer’s disease in vivo, to evaluate the production of β-amyloid precursor protein (APP) upon RAGE and CD147 modulation in the cerebral vascular endothelium as part of the BBB model in vitro. Methods. Male mice of lines the B6SLJ-Tg(APPSwFlLon, PSEN1 * M146L * L286V) 6799Vas (genetic model of Alzheimer’s disease) and C57BL / 6 (control group) at the age of 9 months. Male mice of the line the C57BL / 6 at the age of 4 months, which were introduced β-amyloid for modeling Alzheimer’s disease, sham-operated animals were used as a control. The expression of β-amyloid in the hippocampus was studied by immunohistochemistry. Quantitative analysis of APP gene expression in vitro was performed by PCR. Results. The expression of β-amyloid in the endothelium of the hippocampus was significantly (р
Keywords: 
cerebral endothelium, APP, β-amyloid, RAGE, CD147, Alzheimer’s disease

Список литературы: 
  1. Harrison T.M., La Joie R., Maass A., Baker S.L., Swinnerton K., Fenton L., Mellinger T.J., Edwards L., Pham J., Miller B.L., Rabinovici G.D., Jagust W.J. Longitudinal tau accumulation and atrophy in aging and Alzheimer disease. Ann Neurol. 2019; 85 (2): 229–40. https://doi.org/10.1002/ana.25406.
  2. Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019; 363 (6428). https://doi.org/10.1126/science.aaw0930.
  3. Pardossi-Piquard R., Checler F. The physiology of the β-amyloid precursor protein intracellular domain AICD. J. Neurochem. 2012; 120: 109–24. https://doi.org/10.1111/j.1471-4159.2011.07475.x.
  4. Zandl-Lang M., Fanaee-Danesh E., Sun Y., Albrecher N.M., Gali C.C., Čančar I., Kober A., Tam-Amersdorfer C., Stracke A., Storck S.M., Saeed A., Stefulj J., Pietrzik C.U., Wilson M.R., Björkhem I., Panzenboeck U. Regulatory effects of simvastatin and apoJ on APP processing and amyloid-β clearance in blood-brain barrier endothelial cells. Biochim Biophys Acta Mol. Cell Biol. Lipids. 2017; 1863 (1): 40–60. https://doi.org/10.1016/j.bbalip.2017.09.008.
  5. Storck S.E., Meister S., Nahrath J., Meißner J.N., Schubert N., Di Spiezio A., Baches S., Vandenbroucke R.E., Bouter Y., Prikulis I., Korth C., Weggen S., Heimann A., Schwaninger M., Bayer T.A., Pietrzik C.U. Endothelial LRP1 transports amyloid-β (1-42) across the blood-brain barrier. J. Clin Invest. 2016; 126 (1): 123–36. https://doi.org/10.1172/JCI81108.
  6. Greenberg S.M., Bacskai B.J., Hernandez-Guillamon M., Pruzin J., Sperling R., van Veluw S.J. Cerebral amyloid angiopathy and Alzheimer disease – one peptide, two pathways. Nat Rev Neurol. 2020; 16 (1): 30–42. https://doi.org/10.1038/s41582-019-0281-2.
  7. Keable A., Fenna K., Yuen H.M., Johnston D.A., Smyth N. R., Smith C., Al-Shahi Salman R, Samarasekera N., Nicoll J.A.R., Attems J., Kalaria R.N., Weller R.O., Carare R.O. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy. Biochim Biophys Acta. 2016; 1862 (5): 1037–46. https://doi.org/10.1016/j.bbadis.2015.08.024.
  8. Han B.H., Zhou M.L., Johnson A.W., Singh I., Liao F., Vellimana A.K., Nelson J.W., Milner E., Cirrito J.R., Basak J., Yoo M., Dietrich H.H., Holtzman D.M., Zipfel G.J. Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proc Natl Acad Sci USA. 2015; 112 (8): 881–90. https://doi.org/10.1073/pnas.1414930112.
  9. Uspenskaja Ju.A., Komleva Ju.K., Gorina Ja.V., Pozhilenkova E.A., Belova O.A., Salmina A.B. Polifunktsional'nost' CD147 i novye vozmozhnosti dlja diagnostiki i terapii. Sibirskoe meditsinskoe obozrenie. 2018; 4: 22–30. https://doi.org/10.20333/2500136-2018-4-22-30. [Uspenskaja Ju.A., Komleva Ju.K., Gorina Ja.V., Pozhilenkova E.A., Belova O.A., Salmina A.B. CD147 polyfunctionality and new diagnostic and therapy opportunities. Sibirskoe medicinskoe obozrenie. 2018; 4: 22–30. https://doi.org/10.20333/2500136-2018-4-22-30 (in Russian)]
  10. Osgood D., Miller M.C., Messier A.A., Gonzalez L., Silverberg G.D. Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier. Neurobiol Aging. 2017; 57: 178–85. https://doi.org/10.1016/j.neurobiolaging.2017.05.011.
  11. Paxinos G., Franklin K. The mouse brain in stereotaxic coordinates. USA: Academic Press. 2004; 360.
  12. Epelbaum S., Youssef I., Lacor P.N., Chaurand P., Duplus E., Brugg B., Duyckaerts C., Delatour B. Acute amnestic encephalopathy in amyloid-β oligomer-injected mice is due to their widespread diffusion in vivo. Neurobiol Aging; 36 (6): 2043–2052. https://doi.org/10.1016/j.neurobiolaging.2015.03.005.
  13. Shi X.Z., Wei X., Sha L.Z., Xu Q. Comparison of β-Amyloid Plaque Labeling Methods: Antibody Staining, Gallyas Silver Staining, and Thioflavin-S Staining. Chin Med Sci J. 2018; 33 (3): 167–73. https://doi.org/10.24920/03476.
  14. Gorina Ja.V., Komleva Ju.K., Lopatina O.L., Chernyh A.I., Salmina A.B. Ekspressija molekul-komponentov insulin-oposredovannoj signal'noj transduktsii v kletkah golovnogo mozga pri eksperimental'noj bolezni Al'tsgejmera. Annaly klinicheskoj i eksperimental'noj nevrologii. 2019; 13 (4): 1–7. https://doi.org/10.25692/ACEN.2019.4.5. [Gorina Ja.V., Komleva Ju.K., Lopatina O.L., Chernyh A.I., Salmina A.B. Molecular expression of insulin signal transduction components in brain cells in an experimental model of Alzheimer’s disease. Annaly klinicheskoj i jeksperimental’noj nevrologii. 2019; 13 (4): 1–7. https://doi.org/10.25692/ACEN.2019.4.5 (in Russian)]
  15. Gorina Ja.V., Komleva Ju.K., Lopatina O.L., Chernyh A.I., Salmina A.B. Povedencheskij fenotipicheskij analiz zhivotnyh s geneticheskoj model'ju bolezni Al'tsgejmera. Biomeditsina. 2017; 3: 47–59. [Gorina Ja.V., Komleva Ju.K., Lopatina O.L., Chernyh A.I., Salmina A.B. Behavioral phenotypic analysis of animals with a genetic model of Alzheimer’s disease. Biomedicina. 2017; 3: 47–59 (in Russian)]
  16. Garcia-Cabezas M.Á., John Y.J., Barbas H., Zikopoulos B. Distinction of Neurons, Glia and Endothelial Cells in the Cerebral Cortex: An Algorithm Based on Cytological Features. Front Neuroanat. 2016; 10: 107. https://doi.org/10.3389/fnana.2016.00107.
  17. Liu Y., Xue Q., Tang Q., Hou M., Qi H., Chen G., Chen W., Zhang J., Chen Y., Xu X. A simple method for isolating and culturing the rat brain microvascular endothelial cells. Microvasc Res. 2013; 90: 199–205. https://doi.org/10.1016/j.mvr.2013.08.004. Epub 2013 Aug 24.
  18. Morgun A.V., Kuvacheva N.V., Komleva Ju.K., Kutischeva I.A., Okuneva O.S., Drobushevskaja A.I., Hilazheva E.D., Cherepanov S.M., Salmina A.B. Differentsirovka embrional'nyh progenitornyh kletok mozga krys v astrotsity i nejrony. Sibirskoe meditsinskoe obozrenie. 2013; 6: 9–12. [Morgun A.V., Kuvacheva N.V., Komleva Ju.K., Kutishheva I.A., Okuneva O.S., Drobushevskaja A.I., Hilazheva E.D., Cherepanov S.M., Salmina A.B. Differentiation of embryonic progenitor cells of rat brain in astrocytes and neurons. Sibirskoe medicinskoe obozrenie. 2013; 6: 9–12 (in Russian)]
  19. Sweeney M.D., Sagare A.P., Zlokovic B.V. Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer’s disease. J. Cereb Blood Flow Metab. 2015; 35 (7): 1055–68. https://doi.org/10.1038/jcbfm.2015.76.
  20. Vijayan M., Kumar S., Bhatti J.S., Reddy P.H. Molecular Links and Biomarkers of Stroke, Vascular Dementia, and Alzheimer’s Disease. Prog Mol. Biol. Transl Sci. 2017; 146: 95–126. https://doi.org/10.1016/bs.pmbts.2016.12.014.
  21. Miao J., Xu F., Davis J., Otte-Höller I., Verbeek M.M., Van Nostrand W.E. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am. J. Pathol. 2005; 167 (2): 505–15. https://doi.org/10.1016/s0002-9440(10)62993-8.
  22. Du H., Li P., Wang J., Qing X., Li W. The interaction of amyloid β and the receptor for advanced glycation endproducts induces matrix metalloproteinase-2 expression in brain endothelial cells. Cell Mol Neurobiol. 2012; 32 (1): 141–7. https://doi.org/10.1007/s10571-011-9744-8.
  23. Kuznetsova E1, Schliebs R. β-Amyloid, cholinergic transmission, and cerebrovascular system – a developmental study in a mouse model of Alzheimer’s disease. Curr Pharm Des. 2013; 19 (38): 6749–65. https://doi.org/10.2174/13816128113199990711.
  24. Attems J., Yamaguchi H., Saido T.C., Thal D.R. Capillary CAA and perivascular Abeta-deposition: two distinct features of Alzheimer’s disease pathology. J. Neurol Sci. 2010; 299 (1–2): 155–62. https://doi.org/10.1016/j.jns.2010.08.030.
  25. Hartz A.M., Bauer B., Soldner E.L., Wolf A., Boy S., Backhaus R., Mihaljevic I., Bogdahn U., Klunemann H.H., Schuierer G., Schlachetzki F. Amyloid-beta contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy. Stroke J. Cereb Circ. 2012; 43 (2): 514–23. https://doi.org/10.1161/STROKEAHA.111.627562.
  26. Rombouts S.A., Goekoop R., Stam C.J., Barkhof F., Scheltens P. Delayed rather than decreased BOLD response as a marker for early Alzheimer’s disease. NeuroImage. 2005; 26 (4): 1078–85. https://doi.org/10.1016/j.neuroimage.2005.03.022.
  27. Bulbarelli A., Lonati E., Brambilla A., Orlando A., Cazzaniga E., Piazza F., Ferrarese C., Masserini M., Sancini G. Abeta42 production in brain capillary endothelial cells after oxygen and glucose deprivation. Mol Cell Neurosci. 2012; 49 (4): 415–22. https://doi.org/10.1016/j.mcn.2012.01.007.
  28. Fonseca A.C.R.G., Ferreiro E., Oliveira C.R., Cardoso S.M., Pereira C.F. Activation of the endoplasmic reticulum stress response by the amyloid-beta 1–40 peptide in brain endothelial cells. BBA Mol Basis Dis. 2013; 1832 (12): 2191–203. https://doi.org/10.1016/j.bbadis.2013.08.007.
  29. Fonseca A.C., Moreira P.I., Oliveira C.R., Cardoso S.M., Pinton P., Pereira C.F. Amyloid-beta disrupts calcium and redox homeostasis in brain endothelial cells. Mol Neurobiol. 2015; 51 (2): 610–22. https://doi.org/10.1007/s12035-014-8740-7.
  30. Miller M.C., Tavares R., Johanson C.E., Hovanesian V., Donahue J.E., Gonzalez L., Silverberg G.D., Stopa E.G. Hippocampal RAGE immunoreactivity in early and advanced Alzheimer’s disease. Brain Res. 2008; 1230: 273–80. https://doi.org/10.1016/j.brainres.2008.06.124.
  31. Zhang S., Hu L., Jiang J., Li H., Wu Q., Ooi K., Wang J., Feng Y., Zhu D., Xia C. HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia. J Neuroinflammation. 2020; 17 (1): 15. https://doi.org/10.1186/s12974-019-1673-3.
  32. Deane R., Singh I., Sagare A.P., Bell R.D., Ross N.T., LaRue B., Love R., Perry S., Paquette N., Deane R.J., Thiyagarajan M., Zarcone T., Fritz G., Friedman A.E., Miller B.L., Zlokovic B.V. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J. Clin. Invest. 2012; 122 (4): 1377–92. https://doi.org/10.1172/JCI58642.
  33. Wan W., Cao L., Liu L., Zhang C., Kalionis B., Tai X., Li Y., Xia S. Aβ (1–42) oligomer-induced leakage in an in vitro blood-brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins. J. Neurochem. 2015; 134 (2): 382–93. https://doi.org/10.1111/jnc.13122.
  34. Vetrivel K.S., Zhang X., Meckler X., Cheng H., Lee S., Gong P., Lopes K.O., Chen Y., Iwata N., Yin K.-J., Lee J.-M., Parent A.T., Saido T.C., Li Y.-M., Sisodia S.S., Thinakaran G. Evidence that CD147 modulation of β-amyloid (Aβ) levels is mediated by extracellular degradation of secreted Aβ. The J. of Biological Chemistry. 2008; 283 (28): 19489–98. https://doi.org/10.1074/jbc.M801037200.
  35. Kanyenda L.J., Verdile G., Boulos S., Krishnaswamy S., Taddei K., Meloni B.P., Mastaglia F.L., Martins R.N. The dynamics of CD147 in Alzheimer’s disease development and pathology. J. Alzheimers Dis. 2011; 26 (4): 593–605. https://doi.org/10.3233/JAD-2011-110584.