Expression of MAPK and inflammasomes in cells of the brain in experimental Alzheimer's disease

Cover Page

Cite item

Full Text


Introduction. Alzheimer's disease is a chronic neurodegenerative disease that leads to neuropsychiatric disorders and decrease in cognitive activity. A number of studies demonstrate the important role of the mitogen-activated protein kinase (MAPK) pathway and inflamasome NLRP3 in disturbing the metabolism of β-amyloid and insulin resistance in Alzheimer's disease.
Objective. To study the expression of NLRP3 on cells of neuronal and glial nature, as well as MAPK on neurons in the amygdala of animals with experimental Alzheimer's disease.
Material and methods. Subjects of the study were: 1) CD1 mice (males, 4 months old) divided in 2 groups, the experimental group (intra-hippocampal
intjection of β-amyloid) and the control group (sham-operated animals); mice with a genetic model of Alzheimer’s disease, the B6SLJ-line Tg (APPSwFlLon, PSEN1*M146L*L286V) 6799Vas (males, 12 months old) and the corresponding control group, C57BL/6xSJL mice (males, 12 months old). Immunohistochemistry on free-floating sections was used to study the expression of NLRP3 and MAPK in the brain amygdala.
Results. It was found that NeuN/NLRP3-positive cells were increased in animals with a genetic model of Alzheimer's disease in the amygdala (29.05±2.67) compared with the control animals (17.10±1.95) (p=0.043). A similar picture was observed in β-amyloid-induced neurodegeneration (p=0.021). Intra-hippocampal injection of β-amyloid caused the decrease of MAPK expression in the amygdala neurons (5.97±0.66) compared with sham-operated animals (13.25±2.65) (p=0.018). A similar situation was observed in animals with a genetic model of Alzheimer's disease (p=0.031).
Conclusion. Increase of expression of inflammasomes NLRP3 was observed on neurons, but not astrocytes, in animals with experimental Alzheimer's disease. Wefound a decrease of the expression of MAPK on neurons in the amygdala. This indicates coupling of the inflammatory process and the disturbances of insulin-signaling mechanisms in the brain in neurodegeneration.

About the authors

Yana V. Gorina

Voyno-Yasenetsky Krasnoyarsk State Medical University

Author for correspondence.
Russian Federation, Krasnoyarsk

Olga L. Lopatina

Voyno-Yasenetsky Krasnoyarsk State Medical University

Russian Federation, Krasnoyarsk

Yuliya K. Komleva

Voyno-Yasenetsky Krasnoyarsk State Medical University

Russian Federation, Krasnoyarsk

Anatolii I. Chernykh

Krasnoyarsk City Hospital No. 20 named after I.S. Berzon

Russian Federation, Krasnoyarsk

Alla B. Salmina

Voyno-Yasenetsky Krasnoyarsk State Medical University

Russian Federation, Krasnoyarsk


  1. Pierce A.L., Bullain S.S., Kawas C.H. Late-Onset Alzheimer Disease. Neurol Clin. 2017; 35: 283–293. doi: 10.1016/j.ncl.2017.01.006. PMID: 28410660.
  2. Fessel J. Amyloid is essential but insufficient for Alzheimer causation: addition of subcellular cofactors is required for dementia. Int J Geriatr Psychiatry. 2017. [Epub ahead of print]. doi: 10.1002/gps.4730. PMID: 28509380.
  3. Gao Y., Tan L., Yu J.T., Tan L. Tau in Alzheimer's disease: Mechanisms and therapeutic strategies. Curr Alzheimer Res. 2017. [Epub ahead of print]. doi: 10.2174/1567205014666170417111859. PMID: 28413986.
  4. Giri M., Zhang M., Lü Y. Genes associated with Alzheimer's disease: an overview and current status. Clin Interv Aging. 2016; 11: 665–681. doi: 10.2147/CIA.S105769. PMID: 27274215.
  5. Waite L.M. Treatment for Alzheimer's disease: has anything changed? Aust Prescr. 2015; 38: 60–63. PMID: 26648618.
  6. Banks W.A., Owen J.B., Erickson M.A. Insulin in the brain: there and back again. Pharmacol Ther. 2012; 136: 82–93. doi: 10.1016/j.pharmthera.2012.07.006. PMID: 22820012.
  7. King G.L., Park K., Li Q. Selective Insulin Resistance and the Development of Cardiovascular Diseases in Diabetes: The 2015 Edwin Bierman Award Lecture. Diabetes. 2016; 65: 1462–1471. doi: 10.2337/db16-0152. PMID: 27222390.
  8. Chen Y., Deng Y., Zhang B., Gong C.X. Deregulation of brain insulin signaling in Alzheimer’s disease. Neurosci Bull. 2014; 30: 282–294. doi: 10.1007/s12264-013-1408-x. PMID: 24652456.
  9. Ghasemi R., Dargahi L., Haeri A. et al. Brain insulin dysregulation: implication for neurological and neuropsychiatric disorders. Mol Neurobiol. 2013; 47: 1045–1065. doi: 10.1007/s12035-013-8404-z. PMID: 23335160.
  10. Tong L., Balazs R., Thornton P.L., Cotman C.W. Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. Journal of Neuroscience. 2004; 24: 6799–6809. doi: 10.1523/JNEUROSCI.5463-03.2004. PMID: 15282285.
  11. Tan M.S., Yu J.T., Jiang T. et al. The NLRP3 inflammasome in Alzheimer's disease. Mol Neurobiol. 2013; 48: 875–882. doi: 10.1007/s12035-013-8475-x. PMID: 23686772.
  12. Wen H., Gris D Lei al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011; 12: 408–415. doi: 10.1038/ni.2022. PMID: 21478880.
  13. Komleva Yu.A., Malinovskaya N.A., Gorina Ya.V. et al. [Expression of CD38 and CD157 molecules in olfactory bulbs of the brain in experimental Alzheimer's disease]. Sibirskoe meditsinskoe obozrenie. 2015; 5: 45-49. (In Russ.)
  14. Encinas J.M., Enikolopov G. Identifying and Quantitating Neural Stem and Progenitor Cells in the Adult Brain. Methods Cell Biol. 2008; 85: 243–272. doi: 10.1016/s0091-679x(08)85011-x. PMID: 18155466.
  15. Prinz M., Priller J., Sisodia S.S., Ransohoff R.M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nature Neurosci. 2011; 14: 1227–1235. doi: 10.1038/nn.2923. PMID: 21952260.
  16. Brough D., Denes A. Interleukin-1alpha and brain inflammation. IUBMB Life 2015; 67: 323–330. doi: 10.1002/iub.1377. PMID: 25906979.
  17. Dinarello C.A. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 2006; 83: 447S–455S. PMID: 16470011.
  18. Heneka M.T., Kummer M.P., Stutz A. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013; 493: 674-678. doi: 10.1038/nature11729. PMID: 23254930.
  19. Kaushal V., Dye R., Pakavathkumar P. et al. Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ. 2015; 22: 1676–1686. doi: 10.1038/cdd.2015.16. PMID: 25744023.
  20. Bergsbaken T., Fink S.L., Cookson B.T. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009; 7: 99–109.
  21. Tan M.S., Tan L., Jiang T. et al. Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease. Cell Death Dis. 2014; 5: e1382. doi: 10.1038/nrmicro2070. PMID: 19148178.
  22. Johann S., Heitzer M., Kanagaratnam M. et al. NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia. 2015; 63: 2260-2273. doi: 10.1002/glia.22891. PMID: 26200799.
  23. Lau L.T., Yu A.C. Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma 2001; 18: 351–359. doi: 10.1089/08977150151071035. PMID: 11284554.
  24. Liu L., Chan C. IPAF inflammasome is involved in interleukin-1beta production from astrocytes, induced by palmitate; implications for Alzheimer’s Disease. Neurobiol Aging 2014; 35: 309–321. doi: 10.1016/j.neurobiolaging.2013.08.016. PMID: 24054992.
  25. Hass D.T., Barnstable C.J. Uncoupling protein 2 in the glial response to stress: implications for neuroprotection. Neural Regen Res. 2016; 11: 1197–1200. doi: 10.4103/1673-5374.189159. PMID: 27651753.
  26. Kothari V., Luo Y., Tornabene T. et al. High fat diet induces brain insulin resistance and cognitive impairment in mice. Biochim Biophys Acta. 2017; 1863: 499–508. doi: 10.1016/j.bbadis.2016.10.006. PMID: 27771511.
  27. Schrijvers E.M., Witteman J.C., Sijbrands E.J. et al. Insulin metabolism and the risk of Alzheimer disease: the Rotterdam Study. Neurology. 2010; 75: 1982–1987. doi: 10.1212/WNL.0b013e3181ffe4f6. PMID: 21115952.
  28. Macesic M., Lalic N.M., Kostic V.S. et al. Impaired Insulin Sensitivity And Secretion In Patients With Alzheimer's Disease: The Relationship With Other Atherosclerosis Risk Factors. Curr Vasc Pharmacol. 2017; 15: 158–166. doi: 10.2174/1570161114666160905170644. PMID: 27599805.
  29. Kandimalla R., Thirumala V., Reddy P.H. Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal. Biochim Biophys Acta. 2017; 1863: 1078–1089. doi: 10.1016/j.bbadis.2016.08.018. PMID: 27567931.
  30. Cusi K., Maezono K., Osman A. et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000; 105:311–320. PMID: 10675357.
  31. Gyurkó M.D., Steták A., Sőti C., Csermely P. Multitarget network strategies to influence memory and forgetting: the Ras/MAPK pathway as a novel option. Mini Rev Med Chem. 2015; 15: 696–704. PMID: 25694072.
  32. Moghbelinejad S., Nassiri-Asl M., Farivar T.N. et al. Rutin activates the MAPK pathway and BDNF gene expression on beta-amyloid induced neurotoxicity in rats. Toxicol Lett. 2014; 224: 108–113. doi: 10.1016/j.toxlet.2013.10.010. PMID: 24148604.
  33. Zeng Y., Zhang L., Hu Z. Cerebral insulin, insulin signaling pathway, and brain angiogenesis. Neurol Sci. 2016; 37: 9–16. doi: 10.1007/s10072-015-2386-8. PMID: 26442674.

Supplementary files

Supplementary Files

Copyright (c) 2017 Gorina Y.V., Lopatina O.L., Komleva Y.К., Chernykh A.I., Salmina A.B.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-83204 от 12.05.2022.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies