ACCUMULATION OF β-AMYLOID LEADS TO A DECREASE IN LYNX1 AND LYPD6B EXPRESSION IN THE HIPPOCAMPUS AND INCREASED EXPRESSION OF PRO-INFLAMMATORY CYTOKINES IN THE HIPPOCAMPUS AND BLOOD SERUM

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Alzheimer’s disease is a rapidly progressive neurodegenerative disease, the development of which is associated with the accumulation of β-amyloid oligomers, dysfunction of the α7-nAChR nicotinic acetylcholine receptor, and activation of inflammation. Previously, we have shown that the neuromodulator Lynx1, which belongs to the Ly6/uPAR family, competes with β-amyloid(1–42) for binding to α7-nAChR. In the present work, we studied the expression and localization of Ly6/uPAR family proteins in the hippocampus of 2xTg-AD transgenic mice that model AD and demonstrate increased amyloidosis in the brain. Using real-time PCR, we showed a decrease in the expression of the genes encoding Lynx1, Lypd6b, and the postsynaptic marker PSD95, as well as an increase in the expression of the TNFα gene in the hippocampus of 2xTg-AD mice. Histochemical analysis revealed that, in the hippocampus of 2xTg-AD mice Lynx1 does not co-localize with α7-nAChR that can lead to the development of pathology when the receptor interacts with oligomeric β-amyloid. Also, in 2xTg-AD mice, activation of systemic inflammation was shown, which manifests itself in a decrease in the serum level of SLURP-1, a Ly6/uPAR family protein capable of regulating inflammatory processes, as well as an increase in the content of pro-inflammatory cytokines TNFα and TNFβ. Thus, α7-nAChR dysfunction and maintenance of the inflammatory microenvironment in the brain in Alzheimer’s disease may be associated with a decrease in the expression of Ly6/uPAR family proteins that regulate α7-nAChR activity and inflammation.

About the authors

M. L. Bychkov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: ekaterina-lyukmanova@yandex.ru
Russian Federation, Moscow

A. V. Kirichenko

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: ekaterina-lyukmanova@yandex.ru
Russian Federation, Moscow

A. S. Paramonov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: ekaterina-lyukmanova@yandex.ru
Russian Federation, Moscow

M. P. Kirpichnikov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; Interdisciplinary Scientific and Educational School “Molecular Technologies of Living Systems and Synthetic Biology”, Faculty of Biology, Lomonosov Moscow State University M.V. Lomonosov

Email: ekaterina-lyukmanova@yandex.ru
Russian Federation, Moscow; Russian Federation, Moscow

E. N. Lukmanova

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; Interdisciplinary Scientific and Educational School “Molecular Technologies of Living Systems and Synthetic Biology”, Faculty of Biology, Lomonosov Moscow State University M.V. Lomonosov; Shenzhen MSU-BIT University

Author for correspondence.
Email: ekaterina-lyukmanova@yandex.ru
Russian Federation, Moscow; Russian Federation, Moscow; China, Shenzhen

References

  1. Ballard C. et al. Alzheimer’s disease // Lancet. 2011. V. 377. № 9770. P. 1019–1031.
  2. Hampel H. et al. The Amyloid-β Pathway in Alzheimer’s Disease // Mol Psychiatry. 2021. V. 26. № 10. P. 5481–5503.
  3. Muralidar S. et al. Role of tau protein in Alzheimer’s disease: The prime pathological player // Int J Biol Macromol. 2020. V. 163. P. 1599–1617.
  4. Buckingham S.D. et al. Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection // Pharmacol. Rev. 2009. V. 61. № 1. P. 39–61.
  5. Lasala M. et al. Molecular Modulation of Human α7 Nicotinic Receptor by Amyloid-β Peptides // Front Cell Neurosci. 2019. V. 13. P. 37.
  6. Thomsen M.S. et al. Lynx1 and Aβ1–42 bind competitively to multiple nicotinic acetylcholine receptor subtypes // Neurobiology of Aging. 2016. V. 46. P. 13–21.
  7. Hernandez C.M. et al. Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer’s disease // J Neurosci. 2010. V. 30. № 7. P. 2442–2453.
  8. Decourt B., Lahiri D.K., Sabbagh M.N. Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease // Curr Alzheimer Res. 2017. V. 14. № 4. P. 412–425.
  9. de Jonge W.J., Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation // Br J Pharmacol. 2007. V. 151. № 7. P. 915–929.
  10. King J.R., Gillevet T.C., Kabbani N. A G protein-coupled α7 nicotinic receptor regulates signaling and TNF-α release in microglia // FEBS Open Bio. 2017. V. 7. № 9. P. 1350–1361.
  11. Miwa J.M. et al. lynx1, an Endogenous Toxin-like Modulator of Nicotinic Acetylcholine Receptors in the Mammalian CNS // Neuron. 1999. V. 23. № 1. P. 105–114.
  12. Shenkarev Z.O. et al. Water-soluble variant of human Lynx1 positively modulates synaptic plasticity and ameliorates cognitive impairment associated with α7-nAChR dysfunction // J Neurochem. 2020. V. 155. № 1. P. 45–61.
  13. Lyukmanova E. et al. Human Secreted Ly-6/uPAR Related Protein-1 (SLURP-1) Is a Selective Allosteric Antagonist of α7 Nicotinic Acetylcholine Receptor // PLOS ONE / ed. Ulrich H. 2016. V. 11. № 2. P. e0149733.
  14. Jensen M.M. et al. Prostate stem cell antigen interacts with nicotinic acetylcholine receptors and is affected in Alzheimer’s disease // Neurobiology of Aging. 2015. V. 36. № 4. P. 1629–1638.
  15. Bychkov M.L. et al. Lynx1 Prevents Long-Term Potentiation Blockade and Reduction of Neuromodulator Expression Caused by Aβ1-42 and JNK Activation // Acta Naturae. 2018. V. 10. № 3. P. 57–61.
  16. Elder G.A. et al. Presenilin transgenic mice as models of Alzheimer’s disease // Brain Struct Funct. 2010. V. 214. № 0. P. 127–143.
  17. Chernyavsky A.I. et al. Anti-Inflammatory Effects of the Nicotinergic Peptides SLURP-1 and SLURP-2 on Human Intestinal Epithelial Cells and Immunocytes // Biomed Res Int. 2014. V. 2014.
  18. Buhrmann C. et al. Evidence that TNF-β (lymphoto-xin α) can activate the inflammatory environment in human chondrocytes // Arthritis Research & Therapy. 2013. V. 15. № 6. P. R202.
  19. Jang D.-I. et al. The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics // Int J Mol Sci. 2021. V. 22. № 5. P. 2719.
  20. Torres-Acosta N. et al. Therapeutic Potential of TNF-α Inhibition for Alzheimer’s Disease Prevention // J Alzheimers Dis. 2020. V. 78. № 2. P. 619–626.

Supplementary files

Supplementary Files
Action
1. JATS XML
2.

Download (332KB)
3.

Download (1MB)
4.

Download (114KB)

This website uses cookies

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

About Cookies