Abstract
Variations in several complement genes are now known to be significant risk factors for the development of age-related macular degeneration (AMD). Despite dramatic effects on disease susceptibility, the underlying mechanisms by which common polymorphisms in complement proteins alter disease risk have remained unclear. Genetically modified mice in which the activity of the complement has been altered are available and can be used to investigate the role of complement in the pathogenesis of AMD. In this mini review, we will discuss some existing complement models of AMD and our efforts to develop and characterize the ocular phenotype in a variety of mice in which complement is either chronically activated or inhibited. A spectrum of complement dysregulation was modeled on the APOE4 AMD mouse model by crossing these mice to complement factor H knockout (cfh−/−) mice to test the impact of excess complement activation, and by crossing them to soluble-complement-receptor-1-related protein y (sCrry) mice, in which sCrry acts as a potent inhibitor of mouse complement acting in a manner similar to CFH. In addition, we have also generated humanized CFH mice expressing normal and risk variants of CFH.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Anderson DH, Mullins RF, Hageman GS, Johnson LV (2002) A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134(3):411–431
Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 20(6):705–732
Johnson LV, Leitner WP, Staples MK, Anderson DH (2001) Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res 73(6):887–896
Zipfel PF, Lauer N, Skerka C (2010) The role of complement in AMD. Adv Exp Med Biol 703:9–24
Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, Hancox LS, Hu J, Ebright JN, Malek G, Hauser MA, Bowes Rickman C, Bok D, Hageman GS, Johnson LV (2010) The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 29(2):95–112
Thurman JM, Holers VM (2006) The central role of the alternative complement pathway in human disease. J Immunol 176(3):1305–1310
Johnson PT, Betts KE, Radeke MJ, Hageman GS, Anderson DH, Johnson LV (2006) Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid. Proc Natl Acad Sci U S A 103(46):17456–17461
Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31(4):424–428
Coffey PJ, Gias C, McDermott CJ, Lundh P, Pickering MC, Sethi C, Bird A, Fitzke FW, Maass A, Chen LL, Holder GE, Luthert PJ, Salt TE, Moss SE, Greenwood J (2007) Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction. Proc Natl Acad Sci U S A 104(42):16651–16656
Lundh von Leithner P, Kam JH, Bainbridge J, Catchpole I, Gough G, Coffey P, Jeffery G (2009) Complement factor h is critical in the maintenance of retinal perfusion. Am J Pathol 175(1):412–421
Foley S, Li B, Dehoff M, Molina H, Holers VM (1993) Mouse Crry/p65 is a regulator of the alternative pathway of complement activation. Eur J Immunol 23(6):1381–1384
Quigg RJ, He C, Lim A, Berthiaume D, Alexander JJ, Kraus D, Holers VM (1998) Transgenic mice overexpressing the complement inhibitor crry as a soluble protein are protected from antibody-induced glomerular injury. J Exp Med 188(7):1321–1331
Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, Masliah E (2002) Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci U S A 99(16):10837–10842
Ding JD, Lin J, Mace BE, Herrmann R, Sullivan P, Bowes Rickman C (2008) Targeting age-related macular degeneration with Alzheimer’s disease based immunotherapies: anti-amyloid-beta antibody attenuates pathologies in an age-related macular degeneration mouse model. Vision Res 48(3):339–345
Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, Anderson DH (2002) The Alzheimer’s A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci U S A 99(18):11830–11835
Ding JD, Kelly U, Smith SG, Groelle M, Bowes Rickman C (2011) Development and characterization of humanized complement factor H (CFH) transgenic mice. Association for Research in Vision and Ophthalmology:Abstract 958
Ufret-Vincenty RL, Aredo B, Liu X, McMahon A, Chen PW, Sun H, Niederkorn JY, Kedzierski W (2010) Transgenic mice expressing variants of complement factor H develop AMD-like retinal findings. Invest Ophthal Vis Sci 51(11):5878–5887
Malek G, Johnson LV, Mace BE, Saloupis P, Schmechel DE, Rickman DW, Toth CA, Sullivan PM, Bowes Rickman C (2005) Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration. Proc Natl Acad Sci U S A 102(33):11900–11905
Ding JD, Johnson LV, Herrmann R, Farsiu S, Smith SG, Groelle M, Mace BE, Sullivan P, Jamison JA, Kelly U, Harrabi O, Bollini SS, Dilley J, Kobayashi D, Kuang B, Li W, Pons J, Lin JC, Rickman CB (2011) Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration. Proc Natl Acad Sci U S A 108(28):E279–E287
Acknowledgments
sCrry and cfh−/− mice were kindly provided by Drs. R. J. Quigg (University of Chicago, IL) and M. Botto (Imperial College, London), respectively. The work of the authors is supported by NIH Grants EY019038, P30 EY005722, an Edward N. & Della L. Thome Memorial Foundation Award, and Research to Prevent Blindness, Inc. Medical Student Fellowship awards to JGC and WZ.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media, LLC
About this paper
Cite this paper
Ding, JD., Kelly, U., Groelle, M., Christenbury, J., Zhang, W., Bowes Rickman, C. (2014). The Role of Complement Dysregulation in AMD Mouse Models. In: Ash, J., Grimm, C., Hollyfield, J., Anderson, R., LaVail, M., Bowes Rickman, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 801. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3209-8_28
Download citation
DOI: https://doi.org/10.1007/978-1-4614-3209-8_28
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-3208-1
Online ISBN: 978-1-4614-3209-8
eBook Packages: MedicineMedicine (R0)