대한의생명과학회지 (Biomedical Science Letters)

  • 제24권4호
  • /
  • Pages.305-310
  • /
  • 2018
  • /
  • 1738-3226(pISSN)
  • /
  • 2288-7415(eISSN)
대한의생명과학회 (The Korean Society for Biomedical Laboratory Sciences)
권호 표지
DOI QR코드

DOI QR Code

Crosstalk Signaling between IFN-γ and TGF-β in Microglia Restores the Defective β-amyloid Clearance Pathway in Aging Mice with Alzheimer's Disease

  • Choi, Go-Eun (Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan)
  • 투고 : 2018.10.24
  • 심사 : 2018.11.15
  • 발행 : 2018.12.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Microglia are emerging as critical regulators of innate immune responses in AD and other neurodegenerative disorders, highlighting the importance of understanding their molecular and cellular mechanisms. We attempted to determine the role of crosstalk signaling between $IFN-{\gamma}$ and $TGF-{\beta}$ in $A{\beta}$ clearance by microglia cells. We used in vitro and in vivo mouse models that recapitulated acute and chronic aspects of microglial responses to $A{\beta}$ peptides. We showed that crosstalk signaling between $TGF-{\beta}$ and Smad2 was an important mediator of neuro-inflammation. These findings suggest that microglial $TGF-{\beta}$ activity enhances the pathological progression to AD. As $TGF-{\beta}$ displays broad regulatory effects on beneficial microglial functions, the activation of inflammatory crosstalk signaling between $TGF-{\beta}$ and Smad2 may be a promising strategy to restore microglial functions, halt the progression of $A{\beta}$-driven pathology, and prevent AD development.

키워드

참고문헌

  1. Blanchette J, Jaramillo M, Olivier M. Signalling events involved in interferon-gamma-inducible macrophage nitric oxide generation. Immunology. 2003. 108: 513-522. https://doi.org/10.1046/j.1365-2567.2003.01620.x
  2. Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron. 1997. 19: 939-945. https://doi.org/10.1016/S0896-6273(00)80974-5
  3. Darvesh S, Cash MK, Reid GA, Martin E, Mitnitski A, Geula C. Butyrylcholinesterase is associated with beta-amyloid plaques in the transgenic APPSWE/PSEN1dE9 mouse model of Alzheimer disease. J Neuropathol Exp Neurol. 2012. 71: 2-14. https://doi.org/10.1097/NEN.0b013e31823cc7a6
  4. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003. 425: 577-584. https://doi.org/10.1038/nature02006
  5. Gough DJ, Levy DE, Johnstone RW, Clarke CJ. IFNgamma signaling-does it mean JAK-STAT? Cytokine Growth Factor Rev. 2008. 19: 383-394. https://doi.org/10.1016/j.cytogfr.2008.08.004
  6. Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng. 2001. 17: 157-165. https://doi.org/10.1016/S1389-0344(01)00067-3
  7. Klegeris A, Bissonnette CJ, McGeer PL. Modulation of human microglia and THP-1 cell toxicity by cytokines endogenous to the nervous system. Neurobiol Aging. 2005. 26: 673-682. https://doi.org/10.1016/j.neurobiolaging.2004.06.012
  8. Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, Frosch MP, Selkoe DJ. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003. 40: 1087-1093. https://doi.org/10.1016/S0896-6273(03)00787-6
  9. Lyons A, Murphy KJ, Clarke R, Lynch MA. Atorvastatin prevents age-related and amyloid-$\beta$-induced microglial activation by blocking interferon-$\gamma$ release from natural killer cells in the brain. J Neuroinflammation. 2011. 31: 27.
  10. Ng YK, Yong VW, Ling EA. Microglial reaction in some CNS nuclei following nerves transection in BALB/c and interferongamma gene knockout mice. Neurosci Lett. 1999. 262: 207-210. https://doi.org/10.1016/S0304-3940(99)00076-2
  11. Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, Haass C, Ghetti B, Czech C, Holscher C, Mathews PM, Jucker M. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 2006. 7: 940-946. https://doi.org/10.1038/sj.embor.7400784
  12. Tichauer J, Flores B, Soler B, Eugenin-von Bernhardi L, Ramirez G, von Bernhardi R. Age-dependent changes on $TGF{\beta}1$ Smad3 pathway modify the pattern of microglial cell activation. Brain Behav Immun. 2014. 37: 187-196. https://doi.org/10.1016/j.bbi.2013.12.018
  13. Tichauer J, von Bernhardi R. Transforming growth factor-$\beta$ stimulates $\beta$ amyloid uptake by microglia through Smad3-dependent mechanisms. J. Neurosci Res. 2012. 90: 1970-1980. https://doi.org/10.1002/jnr.23082
  14. Ulloa L, Doody J, Massague J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature. 1999. 397: 710-713. https://doi.org/10.1038/17826