Advances in immunoinflammatory regulation of β amyloid in age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

Huang Xiaoxu ,  Sun Xiaodong

Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China;

Corresponding author：

Sun Xiaodong, Email: xdsun@sjtu.edu.cn

Keywords：

Macular degeneration; Amyloid beta-peptides; Immunomodulation; Inflammation; Review

DOI：

10.3760/cma.j.cn511434-20201113-00556

Video：

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Abstract Full text Figures/Tables Video References Cited by

Age-related macular degeneration (AMD) is an age-related degenerative disease with complex pathogenesis, whose initial lesion is accompanied with immune inflammatory response. Amyloid beta (Aβ), a small-molecule protein generated by the hydrolysis of amyloid precursor protein, as the main component, is involved in the formation of drusen, which serves as the early characteristic of AMD. In the local inflammatory response of AMD, Aβ is an important pathological deposit, promoting the proliferation and differentiation of macrophages as well as changing their morphology to accelerate the progression of AMD. In addition, Aβ can also regulate immune molecules and the complement system by activating inflammatory pathways, thus mediating chronic retinal inflammation and promoting the course of AMD. However, since AMD is not caused by inflammation alone, only the immunosuppression may not be effective in inhibiting the course of AMD, and thus the future development is to rebalance the disordered immune system in AMD patients eyes.

Citation： Huang Xiaoxu, Sun Xiaodong. Advances in immunoinflammatory regulation of β amyloid in age-related macular degeneration. Chinese Journal of Ocular Fundus Diseases, 2021, 37(12): 969-973. doi: 10.3760/cma.j.cn511434-20201113-00556 Copy

1.	Datta S, Cano M, Ebrahimi K, et al. The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD[J]. Prog Retin Eye Res, 2017, 60: 201-218. DOI: 10.1016/j.preteyeres.2017.03.002.
2.	Jo DH, Cho CS, Kim JH, et al. Intracellular amyloid-β disrupts tight junctions of the retinal pigment epithelium via NF-κB activation[J]. Neurobiol Aging, 2020, 95: 115-122. DOI: 10.1016/j.neurobiolaging.2020.07.013.
3.	杨宸, 尹莉莉. 7-酮胆固醇在老年性黄斑变性发生发展中的作用研究现状[J]. 中华眼底病杂志, 2017, 33(6): 659-661. DOI: 10.3760/cma.j.issn.1005-1015.2017.06.031.Yang C, Yin LL. The role of 7-ketocholesterol in age-related macular degeneration[J]. Chin J Ocul Fundus Dis, 2017, 33(6): 659-661. DOI: 10.3760/cma.j.issn.1005-1015.2017.06.031.
4.	Busche MA, Hyman BT. Synergy between amyloid-β and tau in Alzheimer's disease[J]. Nat Neurosci, 2020, 23(10): 1183-1193. DOI: 10.1038/s41593-020-0687-6.
5.	Löffler KU, Edward DP, Tso MO. Immunoreactivity against tau, amyloid precursor protein, and beta-amyloid in the human retina[J]. Invest Ophthalmol Vis Sci, 1995, 36(1): 24-31.
6.	Crabb JW, Miyagi M, Gu X, et al. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration[J]. Proc Natl Acad Sci USA, 2002, 99(23): 14682-14687. DOI: 10.1073/pnas.222551899.
7.	Mullins RF, Russell SR, Anderson DH, et al. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease[J]. FASEB J, 2000, 14(7): 835-846. DOI: 10.1096/fasebj.14.7.835.
8.	Dentchev T, Milam AH, Lee VM, et al. Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas[J]. Mol Vis, 2003, 9: 184-190.
9.	Do KV, Kautzmann MI, Jun B, et al. Elovanoids counteract oligomeric β-amyloid-induced gene expression and protect photoreceptors[J]. Proc Natl Acad Sci USA, 2019, 116(48): 24317-24325. DOI: 10.1073/pnas.1912959116.
10.	Klein R, Klein BE, Tomany SC, et al. Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study[J]. Am J Epidemiol, 2002, 156(7): 589-598. DOI: 10.1093/aje/kwf092.
11.	Cao L, Wang H, Wang F. Amyloid-β-induced matrix metalloproteinase-9 secretion is associated with retinal pigment epithelial barrier disruption[J]. Int J Mol Med, 2013, 31(5): 1105-1112. DOI: 10.3892/ijmm.2013.1310.
12.	Liu Y, Dai Y, Li Q, et al. Beta-amyloid activates NLRP3 inflammasome via TLR4 in mouse microglia[J/OL]. Neurosci Lett, 2020, 736: 135279[2020-09-25]. https://pubmed.ncbi.nlm.nih.gov/32726591/. DOI: 10.1016/j.neulet.2020.135279.
13.	Rathnasamy G, Foulds WS, Ling EA, et al. Retinal microglia-a key player in healthy and diseased retina[J]. Prog Neurobiol, 2019, 173: 18-40. DOI: 10.1016/j.pneurobio.2018.05.006.
14.	Iaccarino HF, Singer AC, Martorell AJ, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia[J]. Nature, 2016, 540(7632): 230-235. DOI: 10.1038/nature20587.
15.	Liu RT, Gao J, Cao S, et al. Inflammatory mediators induced by amyloid-beta in the retina and RPE in vivo: implications for inflammasome activation in age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2013, 54(3): 2225-2237. DOI: 10.1167/iovs.12-10849.
16.	Nebel C, Aslanidis A, Rashid K, et al. Activated microglia trigger inflammasome activation and lysosomal destabilization in human RPE cells[J]. Biochem Biophys Res Commun, 2017, 484(3): 681-686. DOI: 10.1016/j.bbrc.2017.01.176.
17.	Miller EB, Zhang P, Ching K, et al. In vivo imaging reveals transient microglia recruitment and functional recovery of photoreceptor signaling after injury[J]. Proc Natl Acad Sci USA, 2019, 116(33): 16603-16612. DOI: 10.1073/pnas.1903336116.
18.	Perez SE, Lumayag S, Kovacs B, et al. Beta-amyloid deposition and functional impairment in the retina of the APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer's disease[J]. Invest Ophthalmol Vis Sci, 2009, 50(2): 793-800. DOI: 10.1167/iovs.08-2384.
19.	Hoh Kam J, Lenassi E, Jeffery G. Viewing ageing eyes: diverse sites of amyloid Beta accumulation in the ageing mouse retina and the up-regulation of macrophages[J/OL]. PLoS One, 2010, 5(10): e13127[2010-10-01]. https://pubmed.ncbi.nlm.nih.gov/20957206/. DOI: 10.1371/journal.pone.0013127.
20.	Lee V, Rekhi E, Hoh Kam J, et al. Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function[J]. Neurobiol Aging, 2012, 33(10): 2382-2389. DOI: 10.1016/j.neurobiolaging.2011.12.002.
21.	Wang K, Yao Y, Zhu X, et al. Amyloid β induces NLRP3 inflammasome activation in retinal pigment epithelial cells via NADPH oxidase- and mitochondria-dependent ROS production[J/OL]. J Biochem Mol Toxicol, 2017, 31(6): E1[2016-12-22]. https://onlinelibrary.wiley.com/doi/10.1002/jbt.21887. DOI: 10.1002/jbt.21887.
22.	Gao J, Liu RT, Cao S, et al. NLRP3 inflammasome: activation and regulation in age-related macular degeneration[J/OL]. Mediators Inflamm, 2015, 2015: 690243[2015-01-27]. https://pubmed.ncbi.nlm.nih.gov/25698849/. DOI: 10.1155/2015/690243.
23.	Lin R, Fu X, Lei C, et al. Intravitreal injection of amyloid β1-42 activates the complement system and induces retinal inflammatory responses and malfunction in mouse[J]. Adv Exp Med Biol, 2019, 1185: 347-352. DOI: 10.1007/978-3-030-27378-1_57.
24.	Cao L, Liu C, Wang F, et al. SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-κB pathway[J]. Braz J Med Biol Res, 2013, 46(8): 659-669. DOI: 10.1590/1414-431X20132903.
25.	Kindzelskii AL, Elner VM, Elner SG, et al. Toll-like receptor 4 (TLR4) of retinal pigment epithelial cells participates in transmembrane signaling in response to photoreceptor outer segments[J]. J Gen Physiol, 2004, 124(2): 139-149. DOI: 10.1085/jgp.200409062.
26.	Ross RJ, Zhou M, Shen D, et al. Immunological protein expression profile in Ccl2/Cx3cr1 deficient mice with lesions similar to age-related macular degeneration[J]. Exp Eye Res, 2008, 86(4): 675-683. DOI: 10.1016/j.exer.2008.01.014.
27.	Chen L, Bai Y, Zhao M, et al. TLR4 inhibitor attenuates amyloid-β-induced angiogenic and inflammatory factors in ARPE-19 cells: implications for age-related macular degeneration[J]. Mol Med Rep, 2016, 13(4): 3249-3256. DOI: 10.3892/mmr.2016.4890.
28.	Jin G, Zou M, Chen A, et al. Prevalence of age-related macular degeneration in Chinese populations worldwide: a systematic review and meta-analysis[J]. Clin Exp Ophthalmol, 2019, 47(8): 1019-1027. DOI: 10.1111/ceo.13580.
29.	Kurji KH, Cui JZ, Lin T, et al. Microarray analysis identifies changes in inflammatory gene expression in response to amyloid-beta stimulation of cultured human retinal pigment epithelial cells[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1151-1163. DOI: 10.1167/iovs.09-3622.
30.	Liu XC, Liu XF, Jian CX, et al. IL-33 is induced by amyloid-β stimulation and regulates inflammatory cytokine production in retinal pigment epithelium cells[J]. Inflammation, 2012, 35(2): 776-784. DOI: 10.1007/s10753-011-9379-4.
31.	Feng L, Cao L, Zhang Y, et al. Detecting Aβ deposition and RPE cell senescence in the retinas of SAMP8 mice[J]. Discov Med, 2016, 21(115): 149-158.
32.	Liu C, Cao L, Yang S, et al. Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration[J]. Int J Mol Med, 2015, 35(1): 169-176. DOI: 10.3892/ijmm.2014.1993.
33.	Cao L, Wang H, Wang F, et al. Aβ-induced senescent retinal pigment epithelial cells create a proinflammatory microenvironment in AMD[J]. Invest Ophthalmol Vis Sci, 2013, 54(5): 3738-3750. DOI: 10.1167/iovs.13-11612.
34.	Yang D, Elner SG, Bian ZM, et al. Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells[J]. Exp Eye Res, 2007, 85(4): 462-472. DOI: 10.1016/j.exer.2007.06.013.
35.	Sun J, Chen J, Li T, et al. ROS production and mitochondrial dysfunction driven by PU. 1-regulated NOX4-p22phox activation in Aβ-induced retinal pigment epithelial cell injury[J]. Theranostics, 2020, 10(25): 11637-11655. DOI: 10.7150/thno.48064.
36.	Wang J, Ohno-Matsui K, Yoshida T, et al. Altered function of factor I caused by amyloid beta: implication for pathogenesis of age-related macular degeneration from Drusen[J]. J Immunol, 2008, 181(1): 712-720. DOI: 10.4049/jimmunol.181.1.712.
37.	Wang J, Ohno-Matsui K, Yoshida T, et al. Amyloid-beta up-regulates complement factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: another mechanism of complement activation in age-related macular degeneration[J]. J Cell Physiol, 2009, 220(1): 119-128. DOI: 10.1002/jcp.21742.
38.	Lashkari K, Teague G, Chen H, et al. A monoclonal antibody targeting amyloid β (Aβ) restores complement factor Ⅰ bioactivity: potential implications in age-related macular degeneration and Alzheimer's disease[J/OL]. PLoS One, 2018, 13(5): e0195751[2018-05-21]. https://pubmed.ncbi.nlm.nih.gov/29782502/. DOI: 10.1371/journal.pone.0195751.
39.	Jiao H, Rutar M, Fernando N, et al. Subretinal macrophages produce classical complement activator C1q leading to the progression of focal retinal degeneration[J]. Mol Neurodegener, 2018, 13(1): 45. DOI: 10.1186/s13024-018-0278-0.
40.	Toomey CB, Johnson LV, Bowes Rickman C. Complement factor H in AMD: bridging genetic associations and pathobiology[J]. Prog Retin Eye Res, 2018, 62: 38-57. DOI: 10.1016/j.preteyeres.2017.09.001.
41.	Zhao T, Gao J, Van J, et al. Age-related increases in amyloid beta and membrane attack complex: evidence of inflammasome activation in the rodent eye[J]. J Neuroinflammation, 2015, 12: 121. DOI: 10.1186/s12974-015-0337-1.
42.	Bian ZM, Elner SG, Yoshida A, et al. Differential involvement of phosphoinositide 3-kinase/Akt in human RPE MCP-1 and IL-8 expression[J]. Invest Ophthalmol Vis Sci, 2004, 45(6): 1887-1896. DOI: 10.1167/iovs.03-0608.
43.	Fernandes AF, Zhou J, Zhang X, et al. Oxidative inactivation of the proteasome in retinal pigment epithelial cells. A potential link between oxidative stress and up-regulation of interleukin-8[J]. J Biol Chem, 2008, 283(30): 20745-20753. DOI: 10.1074/jbc.M800268200.
44.	Doyle SL, Campbell M, Ozaki E, et al. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components[J]. Nat Med, 2012, 18(5): 791-798. DOI: 10.1038/nm.2717.
45.	Webster SD, Yang AJ, Margol L, et al. Complement component C1q modulates the phagocytosis of Abeta by microglia[J]. Exp Neurol, 2000, 161(1): 127-138. DOI: 10.1006/exnr.1999.7260.

1. Datta S, Cano M, Ebrahimi K, et al. The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD[J]. Prog Retin Eye Res, 2017, 60: 201-218. DOI: 10.1016/j.preteyeres.2017.03.002.
2. Jo DH, Cho CS, Kim JH, et al. Intracellular amyloid-β disrupts tight junctions of the retinal pigment epithelium via NF-κB activation[J]. Neurobiol Aging, 2020, 95: 115-122. DOI: 10.1016/j.neurobiolaging.2020.07.013.
3. 杨宸, 尹莉莉. 7-酮胆固醇在老年性黄斑变性发生发展中的作用研究现状[J]. 中华眼底病杂志, 2017, 33(6): 659-661. DOI: 10.3760/cma.j.issn.1005-1015.2017.06.031.Yang C, Yin LL. The role of 7-ketocholesterol in age-related macular degeneration[J]. Chin J Ocul Fundus Dis, 2017, 33(6): 659-661. DOI: 10.3760/cma.j.issn.1005-1015.2017.06.031.
4. Busche MA, Hyman BT. Synergy between amyloid-β and tau in Alzheimer's disease[J]. Nat Neurosci, 2020, 23(10): 1183-1193. DOI: 10.1038/s41593-020-0687-6.
5. Löffler KU, Edward DP, Tso MO. Immunoreactivity against tau, amyloid precursor protein, and beta-amyloid in the human retina[J]. Invest Ophthalmol Vis Sci, 1995, 36(1): 24-31.
6. Crabb JW, Miyagi M, Gu X, et al. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration[J]. Proc Natl Acad Sci USA, 2002, 99(23): 14682-14687. DOI: 10.1073/pnas.222551899.
7. Mullins RF, Russell SR, Anderson DH, et al. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease[J]. FASEB J, 2000, 14(7): 835-846. DOI: 10.1096/fasebj.14.7.835.
8. Dentchev T, Milam AH, Lee VM, et al. Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas[J]. Mol Vis, 2003, 9: 184-190.
9. Do KV, Kautzmann MI, Jun B, et al. Elovanoids counteract oligomeric β-amyloid-induced gene expression and protect photoreceptors[J]. Proc Natl Acad Sci USA, 2019, 116(48): 24317-24325. DOI: 10.1073/pnas.1912959116.
10. Klein R, Klein BE, Tomany SC, et al. Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study[J]. Am J Epidemiol, 2002, 156(7): 589-598. DOI: 10.1093/aje/kwf092.
11. Cao L, Wang H, Wang F. Amyloid-β-induced matrix metalloproteinase-9 secretion is associated with retinal pigment epithelial barrier disruption[J]. Int J Mol Med, 2013, 31(5): 1105-1112. DOI: 10.3892/ijmm.2013.1310.
12. Liu Y, Dai Y, Li Q, et al. Beta-amyloid activates NLRP3 inflammasome via TLR4 in mouse microglia[J/OL]. Neurosci Lett, 2020, 736: 135279[2020-09-25]. https://pubmed.ncbi.nlm.nih.gov/32726591/. DOI: 10.1016/j.neulet.2020.135279.
13. Rathnasamy G, Foulds WS, Ling EA, et al. Retinal microglia-a key player in healthy and diseased retina[J]. Prog Neurobiol, 2019, 173: 18-40. DOI: 10.1016/j.pneurobio.2018.05.006.
14. Iaccarino HF, Singer AC, Martorell AJ, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia[J]. Nature, 2016, 540(7632): 230-235. DOI: 10.1038/nature20587.
15. Liu RT, Gao J, Cao S, et al. Inflammatory mediators induced by amyloid-beta in the retina and RPE in vivo: implications for inflammasome activation in age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2013, 54(3): 2225-2237. DOI: 10.1167/iovs.12-10849.
16. Nebel C, Aslanidis A, Rashid K, et al. Activated microglia trigger inflammasome activation and lysosomal destabilization in human RPE cells[J]. Biochem Biophys Res Commun, 2017, 484(3): 681-686. DOI: 10.1016/j.bbrc.2017.01.176.
17. Miller EB, Zhang P, Ching K, et al. In vivo imaging reveals transient microglia recruitment and functional recovery of photoreceptor signaling after injury[J]. Proc Natl Acad Sci USA, 2019, 116(33): 16603-16612. DOI: 10.1073/pnas.1903336116.
18. Perez SE, Lumayag S, Kovacs B, et al. Beta-amyloid deposition and functional impairment in the retina of the APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer's disease[J]. Invest Ophthalmol Vis Sci, 2009, 50(2): 793-800. DOI: 10.1167/iovs.08-2384.
19. Hoh Kam J, Lenassi E, Jeffery G. Viewing ageing eyes: diverse sites of amyloid Beta accumulation in the ageing mouse retina and the up-regulation of macrophages[J/OL]. PLoS One, 2010, 5(10): e13127[2010-10-01]. https://pubmed.ncbi.nlm.nih.gov/20957206/. DOI: 10.1371/journal.pone.0013127.
20. Lee V, Rekhi E, Hoh Kam J, et al. Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function[J]. Neurobiol Aging, 2012, 33(10): 2382-2389. DOI: 10.1016/j.neurobiolaging.2011.12.002.
21. Wang K, Yao Y, Zhu X, et al. Amyloid β induces NLRP3 inflammasome activation in retinal pigment epithelial cells via NADPH oxidase- and mitochondria-dependent ROS production[J/OL]. J Biochem Mol Toxicol, 2017, 31(6): E1[2016-12-22]. https://onlinelibrary.wiley.com/doi/10.1002/jbt.21887. DOI: 10.1002/jbt.21887.
22. Gao J, Liu RT, Cao S, et al. NLRP3 inflammasome: activation and regulation in age-related macular degeneration[J/OL]. Mediators Inflamm, 2015, 2015: 690243[2015-01-27]. https://pubmed.ncbi.nlm.nih.gov/25698849/. DOI: 10.1155/2015/690243.
23. Lin R, Fu X, Lei C, et al. Intravitreal injection of amyloid β1-42 activates the complement system and induces retinal inflammatory responses and malfunction in mouse[J]. Adv Exp Med Biol, 2019, 1185: 347-352. DOI: 10.1007/978-3-030-27378-1_57.
24. Cao L, Liu C, Wang F, et al. SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-κB pathway[J]. Braz J Med Biol Res, 2013, 46(8): 659-669. DOI: 10.1590/1414-431X20132903.
25. Kindzelskii AL, Elner VM, Elner SG, et al. Toll-like receptor 4 (TLR4) of retinal pigment epithelial cells participates in transmembrane signaling in response to photoreceptor outer segments[J]. J Gen Physiol, 2004, 124(2): 139-149. DOI: 10.1085/jgp.200409062.
26. Ross RJ, Zhou M, Shen D, et al. Immunological protein expression profile in Ccl2/Cx3cr1 deficient mice with lesions similar to age-related macular degeneration[J]. Exp Eye Res, 2008, 86(4): 675-683. DOI: 10.1016/j.exer.2008.01.014.
27. Chen L, Bai Y, Zhao M, et al. TLR4 inhibitor attenuates amyloid-β-induced angiogenic and inflammatory factors in ARPE-19 cells: implications for age-related macular degeneration[J]. Mol Med Rep, 2016, 13(4): 3249-3256. DOI: 10.3892/mmr.2016.4890.
28. Jin G, Zou M, Chen A, et al. Prevalence of age-related macular degeneration in Chinese populations worldwide: a systematic review and meta-analysis[J]. Clin Exp Ophthalmol, 2019, 47(8): 1019-1027. DOI: 10.1111/ceo.13580.
29. Kurji KH, Cui JZ, Lin T, et al. Microarray analysis identifies changes in inflammatory gene expression in response to amyloid-beta stimulation of cultured human retinal pigment epithelial cells[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1151-1163. DOI: 10.1167/iovs.09-3622.
30. Liu XC, Liu XF, Jian CX, et al. IL-33 is induced by amyloid-β stimulation and regulates inflammatory cytokine production in retinal pigment epithelium cells[J]. Inflammation, 2012, 35(2): 776-784. DOI: 10.1007/s10753-011-9379-4.
31. Feng L, Cao L, Zhang Y, et al. Detecting Aβ deposition and RPE cell senescence in the retinas of SAMP8 mice[J]. Discov Med, 2016, 21(115): 149-158.
32. Liu C, Cao L, Yang S, et al. Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration[J]. Int J Mol Med, 2015, 35(1): 169-176. DOI: 10.3892/ijmm.2014.1993.
33. Cao L, Wang H, Wang F, et al. Aβ-induced senescent retinal pigment epithelial cells create a proinflammatory microenvironment in AMD[J]. Invest Ophthalmol Vis Sci, 2013, 54(5): 3738-3750. DOI: 10.1167/iovs.13-11612.
34. Yang D, Elner SG, Bian ZM, et al. Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells[J]. Exp Eye Res, 2007, 85(4): 462-472. DOI: 10.1016/j.exer.2007.06.013.
35. Sun J, Chen J, Li T, et al. ROS production and mitochondrial dysfunction driven by PU. 1-regulated NOX4-p22phox activation in Aβ-induced retinal pigment epithelial cell injury[J]. Theranostics, 2020, 10(25): 11637-11655. DOI: 10.7150/thno.48064.
36. Wang J, Ohno-Matsui K, Yoshida T, et al. Altered function of factor I caused by amyloid beta: implication for pathogenesis of age-related macular degeneration from Drusen[J]. J Immunol, 2008, 181(1): 712-720. DOI: 10.4049/jimmunol.181.1.712.
37. Wang J, Ohno-Matsui K, Yoshida T, et al. Amyloid-beta up-regulates complement factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: another mechanism of complement activation in age-related macular degeneration[J]. J Cell Physiol, 2009, 220(1): 119-128. DOI: 10.1002/jcp.21742.
38. Lashkari K, Teague G, Chen H, et al. A monoclonal antibody targeting amyloid β (Aβ) restores complement factor Ⅰ bioactivity: potential implications in age-related macular degeneration and Alzheimer's disease[J/OL]. PLoS One, 2018, 13(5): e0195751[2018-05-21]. https://pubmed.ncbi.nlm.nih.gov/29782502/. DOI: 10.1371/journal.pone.0195751.
39. Jiao H, Rutar M, Fernando N, et al. Subretinal macrophages produce classical complement activator C1q leading to the progression of focal retinal degeneration[J]. Mol Neurodegener, 2018, 13(1): 45. DOI: 10.1186/s13024-018-0278-0.
40. Toomey CB, Johnson LV, Bowes Rickman C. Complement factor H in AMD: bridging genetic associations and pathobiology[J]. Prog Retin Eye Res, 2018, 62: 38-57. DOI: 10.1016/j.preteyeres.2017.09.001.
41. Zhao T, Gao J, Van J, et al. Age-related increases in amyloid beta and membrane attack complex: evidence of inflammasome activation in the rodent eye[J]. J Neuroinflammation, 2015, 12: 121. DOI: 10.1186/s12974-015-0337-1.
42. Bian ZM, Elner SG, Yoshida A, et al. Differential involvement of phosphoinositide 3-kinase/Akt in human RPE MCP-1 and IL-8 expression[J]. Invest Ophthalmol Vis Sci, 2004, 45(6): 1887-1896. DOI: 10.1167/iovs.03-0608.
43. Fernandes AF, Zhou J, Zhang X, et al. Oxidative inactivation of the proteasome in retinal pigment epithelial cells. A potential link between oxidative stress and up-regulation of interleukin-8[J]. J Biol Chem, 2008, 283(30): 20745-20753. DOI: 10.1074/jbc.M800268200.
44. Doyle SL, Campbell M, Ozaki E, et al. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components[J]. Nat Med, 2012, 18(5): 791-798. DOI: 10.1038/nm.2717.
45. Webster SD, Yang AJ, Margol L, et al. Complement component C1q modulates the phagocytosis of Abeta by microglia[J]. Exp Neurol, 2000, 161(1): 127-138. DOI: 10.1006/exnr.1999.7260.

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