The aging eye: Common degenerative mechanisms between the Alzheimer's brain and retinal disease

Investigative Ophthalmology and Visual Science

Volumn 54, Issue 1, 2013, Pages 871-880

  Sivak, Jeremy M ^a,b  

^a UNIVERSITY HEALTH NETWORK   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; ANTIOXIDANT; LIPOFUSCIN; MEMANTINE; NEUROPROTECTIVE AGENT; TAU PROTEIN; TRACE ELEMENT;

AGING; ALZHEIMER DISEASE; AMYLOID PLAQUE; ANTIINFLAMMATORY ACTIVITY; CEREBROSPINAL FLUID; DEMENTIA; DISEASE COURSE; DRUSEN; EXCITOTOXICITY; GLAUCOMA; GLIOSIS; HOMEOSTASIS; HUMAN; INTRAOCULAR HYPERTENSION; NEUROFIBRILLARY TANGLE; NEUROPROTECTION; NONHUMAN; OPTIC NERVE DISEASE; OXIDATIVE STRESS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN DEGRADATION; RETINA EDEMA; RETINA MACULA AGE RELATED DEGENERATION; REVIEW; SENILE PLAQUE; SUBRETINAL NEOVASCULARIZATION;

AGING; ALZHEIMER DISEASE; ANIMALS; GLAUCOMA; HUMANS; NERVE DEGENERATION; RETINAL DISEASES;

EID: 84874743342     PISSN: 01460404     EISSN: 15525783     Source Type: Journal    
DOI: 10.1167/iovs.12-10827     Document Type: Review

References (161)

1. Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the "common" neurologic disorders? Neurology. 2007;68:326-337.
2. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement. 2007;3:186-191.
3. Jack CR Jr. Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. Radiology. 2012;263:344-361.
4. Thal LJ, Kantarci K, Reiman EM, et al. The role of biomarkers in clinical trials for Alzheimer disease. Alzheimer Dis Assoc Disord. 2006;20:6-15.
5. Cronin-Golomb A, Corkin S, Rizzo JF, Cohen J, Growdon JH, Banks KS. Visual dysfunction in Alzheimer's disease: relation to normal aging. Ann Neurol. 1991;29:41-52.
6. Mendola JD, Cronin-Golomb A, Corkin S, Growdon JH. Prevalence of visual deficits in Alzheimer's disease. Optom Vis Sci. 1995;72:155-167.
7. Rizzo M, Anderson SW, Dawson J, Nawrot M. Vision and cognition in Alzheimer's disease. Neuropsychologia. 2000; 38:1157-1169.
8. Mendez MF, Mendez MA, Martin R, Smyth KA, Whitehouse PJ. Complex visual disturbances in Alzheimer's disease. Neurology. 1990;40:439-443.
9. Uhlmann RF, Larson EB, Koepsell TD, Rees TS, Duckert LG. Visual impairment and cognitive dysfunction in Alzheimer's disease. J Gen Intern Med. 1991;6:126-132.
10. Tsolaki F, Gogaki E, Tiganita S, et al. Alzheimer's disease and primary open-angle glaucoma: is there a connection? Clin Ophthalmol. 2011;5:887-890.
11. McKinnon SJ. The cell and molecular biology of glaucoma: common neurodegenerative pathways and relevance to glaucoma. Invest Ophthalmol Vis Sci. 2012;53:2485-2487.
12. Ohno-Matsui K. Parallel findings in age-related macular degeneration and Alzheimer's disease. Prog Retin Eye Res. 2011;30:217-238.
13. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262-267.
14. Resnikoff S, Pascolini D, Etya'ale D, et al. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004;82:844-851.
15. Flammer J, Mozaffarieh M. What is the present pathogenetic concept of glaucomatous optic neuropathy? Surv Ophthalmol. 2007;52(suppl 2):S162-S173.
16. Lee DA, Higginbotham EJ. Glaucoma and its treatment: a review. Am J Health Syst Pharm. 2005;62:691-699.
17. Tezel G. The role of glia, mitochondria, and the immune system in glaucoma. Invest Ophthalmol Vis Sci. 2009;50: 1001-1012.
18. Gupta N, Greenberg G, de Tilly LN, Gray B, Polemidiotis M, Yucel YH. Atrophy of the lateral geniculate nucleus in human glaucoma detected by magnetic resonance imaging. Br J Ophthalmol. 2009;93:56-60.
19. Yucel Y, Gupta N. Glaucoma of the brain: a disease model for the study of transsynaptic neural degeneration. Prog Brain Res. 2008;173:465-478.
20. Klein BE, Klein R, Sponsel WE, et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology. 1992;99:1499-1504.
21. Millar WJ. Vision problems among seniors. Health Rep. 2004; 16:45-49.
22. Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-1279.
23. Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121:48-56.
24. Shields MB. Normal-tension glaucoma: is it different from primary open-angle glaucoma? Curr Opin Ophthalmol. 2008; 19:85-88.
25. Moore D, Harris A, Wudunn D, Kheradiya N, Siesky B. Dysfunctional regulation of ocular blood flow: a risk factor for glaucoma? Clin Ophthalmol. 2008;2:849-861.
26. Orgul S. Blood flow in glaucoma. Br J Ophthalmol. 2007;91: 3-5.
27. Tezel G, Wax MB. Hypoxia-inducible factor 1alpha in the glaucomatous retina and optic nerve head. Arch Ophthalmol. 2004;122:1348-1356.
28. Bayer AU, Ferrari F, Erb C. High occurrence rate of glaucoma among patients with Alzheimer's disease. Eur Neurol. 2002; 47:165-168.
29. Chandra V, Bharucha NE, Schoenberg BS. Conditions associated with Alzheimer's disease at death: case-control study. Neurology. 1986;36:209-211.
30. Tamura H, Kawakami H, Kanamoto T, et al. High frequency of open-angle glaucoma in Japanese patients with Alzheimer's disease. J Neurol Sci. 2006;246:79-83.
31. Yochim BP, Mueller AE, Kane KD, Kahook MY. Prevalence of cognitive impairment, depression, and anxiety symptoms among older adults with glaucoma. J Glaucoma. 2012;21: 250-254.
32. Kessing LV, Lopez AG, Andersen PK, Kessing SV. No increased risk of developing Alzheimer disease in patients with glaucoma. J Glaucoma. 2007;16:47-51.
33. Bach-Holm D, Kessing SV, Mogensen U, Forman JL, Andersen PK, Kessing LV. Normal tension glaucoma and Alzheimer disease: comorbidity? Acta Ophthalmol. 2011;90:683-685.
34. Blanks JC, Torigoe Y, Hinton DR, Blanks RH. Retinal pathology in Alzheimer's disease. I. Ganglion cell loss in foveal/parafoveal retina. Neurobiol Aging. 1996;17:377-384.
35. Blanks JC, Schmidt SY, Torigoe Y, Porrello KV, Hinton DR, Blanks RH. Retinal pathology in Alzheimer's disease. II. Regional neuron loss and glial changes in GCL. Neurobiol Aging. 1996;17:385-395.
36. Hedges TR III, Perez Galves R, Speigelman D, Barbas NR, Peli E, Yardley CJ. Retinal nerve fiber layer abnormalities in Alzheimer's disease. Acta Ophthalmol Scand. 1996;74:271-275.
37. Berisha F, Feke GT, Trempe CL, McMeel JW, Schepens CL. Retinal abnormalities in early Alzheimer's disease. Invest Ophthalmol Vis Sci. 2007;48:2285-2289.
38. Gupta N, Fong J, Ang LC, Yucel YH. Retinal tau pathology in human glaucomas. Can J Ophthalmol. 2008;43:53-60.
39. Loeffler KU, Edward DP, Tso MO. Tau-2 immunoreactivity of corpora amylacea in the human retina and optic nerve. Invest Ophthalmol Vis Sci. 1993;34:2600-2603.
40. Yoneda S, Hara H, Hirata A, Fukushima M, Inomata Y, Tanihara H. Vitreous fluid levels of beta-amyloid(1-42) and tau in patients with retinal diseases. Jpn J Ophthalmol. 2005; 49:106-108.
41. Leger F, Fernagut PO, Canron MH, et al. Protein aggregation in the aging retina. J Neuropathol Exp Neurol. 2011;70:63-68.
42. Reddy PH. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer's disease. Brain Res. 2011;1415: 136-148.
43. Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res. 2012;31:152-181.
44. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid betapeptide. Nat Rev Mol Cell Biol. 2007;8:101-112.
45. Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J. The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology. 2004;62:1984-1989.
46. Sunderland T, Linker G, Mirza N, et al. Decreased betaamyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA. 2003;289:2094-2103.
47. Janciauskiene S, Westin K, Grip O, Krakau T. Detection of Alzheimer peptides and chemokines in the aqueous humor. Eur J Ophthalmol. 2011;21:104-111.
48. Guo L, Salt TE, Luong V, et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci U S A. 2007;104: 13444-13449.
49. McKinnon SJ, Lehman DM, Kerrigan-Baumrind LA, et al. Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. Invest Ophthalmol Vis Sci. 2002;43: 1077-1087.
50. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992;256:184-185.
51. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10: 698-712.
52. Chiu K, Chan TF, Wu A, Leung IY, So KF, Chang RC. Neurodegeneration of the retina in mouse models of Alzheimer's disease: what can we learn from the retina? Age (Dordr). 2012;34:633-649.
53. Gasparini L, Crowther RA, Martin KR, et al. Tau inclusions in retinal ganglion cells of human P301S tau transgenic mice: effects on axonal viability. Neurobiol Aging. 2011;32:419-433.
54. Liu B, Rasool S, Yang Z, et al. Amyloid-peptide vaccinations reduce {beta}-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer's transgenic mice. Am J Pathol. 2009;175:2099-2110.
55. Ning A, Cui J, To E, Ashe KH, Matsubara J. Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Invest Ophthalmol Vis Sci. 2008;49:5136-5143.
56. Perez SE, Lumayag S, Kovacs B, Mufson EJ, Xu S. Beta-amyloid deposition and functional impairment in the retina of the APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer's disease. Invest Ophthalmol Vis Sci. 2009;50:793-800.
57. Barres B, Dowling JE, Masland R, et al. Astrocytes and Glaucomatous Neurodegeneration: A Report by the Lasker/ IRRF Initiative for Innovation in Vision Science. Albert and Mary Lasker Foundation/International Retinal Research Foundation; 2010.
58. Hernandez MR, Miao H, Lukas T. Astrocytes in glaucomatous optic neuropathy. Prog Brain Res. 2008;173:353-373.
59. Parpura V, Heneka MT, Montana V, et al. Glial cells in (patho)physiology. J Neurochem. 2012;121:4-27.
60. Hernandez MR, Igoe F, Neufeld AH. Cell culture of the human lamina cribrosa. Invest Ophthalmol Vis Sci. 1988;29:78-89.
61. Johnson EC, Morrison JC, Farrell S, Deppmeier L, Moore CG, McGinty MR. The effect of chronically elevated intraocular pressure on the rat optic nerve head extracellular matrix. Exp Eye Res. 1996;62:663-674.
62. Rogers RS, Dharsee M, Ackloo S, Sivak JM, Flanagan JG. Proteomics analyses of human optic nerve head astrocytes following biomechanical strain. Mol Cell Proteomics. 2012; 11:M111.012302.
63. Bignami A, Dahl D. The radial glia of Muller in the rat retina and their response to injury. An immunofluorescence study with antibodies to the glial fibrillary acidic (GFA) protein. Exp Eye Res. 1979;28:63-69.
64. Tanihara H, Hangai M, Sawaguchi S, et al. Up-regulation of glial fibrillary acidic protein in the retina of primate eyes with experimental glaucoma. Arch Ophthalmol. 1997;115:752-756.
65. Cagnin A, Brooks DJ, Kennedy AM, et al. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358: 461-467.
66. Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease. Glia. 2010; 58:831-838.
67. Heneka MT, Wiesinger H, Dumitrescu-Ozimek L, Riederer P, Feinstein DL, Klockgether T. Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J Neuropathol Exp Neurol. 2001;60:906-916.
68. Koistinaho M, Lin S, Wu X, et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med. 2004;10:719-726.
69. Neufeld AH. Microglia in the optic nerve head and the region of parapapillary chorioretinal atrophy in glaucoma. Arch Ophthalmol. 1999;117:1050-1056.
70. Fan W, Li X, Wang W, Mo JS, Kaplan H, Cooper NG. Early involvement of immune/inflammatory response genes in retinal degeneration in DBA/2J mice. Ophthalmol Eye Dis. 2010;1:23-41.
71. Wang X, Tay SS, Ng YK. An immunohistochemical study of neuronal and glial cell reactions in retinae of rats with experimental glaucoma. Exp Brain Res. 2000;132:476-484.
72. Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci. 2003;23:1605-1611.
73. Mrak RE. Microglia in Alzheimer brain: a neuropathological perspective. Int J Alzheimers Dis. 2012;2012:165021.
74. Friedman DS, O'Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122:564-572.
75. Klein R, Peto T, Bird A, Vannewkirk MR. The epidemiology of age-related macular degeneration. Am J Ophthalmol. 2004; 137:486-495.
76. de Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355:1474-1485.
77. Sparrow JR. Bisretinoids of RPE lipofuscin: trigger for complement activation in age-related macular degeneration. Adv Exp Med Biol. 2010;703:63-74.
78. Bressler SB, Maguire MG, Bressler NM, Fine SL. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Photocoagulation Study Group. Arch Ophthalmol. 1990;108:1442-1447.
79. Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-Valckenberg S. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 2007; 143:463-472.
80. Pauleikhoff D, Barondes MJ, Minassian D, Chisholm IH, Bird AC. Drusen as risk factors in age-related macular disease. Am J Ophthalmol. 1990;109:38-43.
81. Atwood CS, Martins RN, Smith MA, Perry G. Senile plaque composition and posttranslational modification of amyloidbeta peptide and associated proteins. Peptides. 2002;23: 1343-1350.
82. 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. PLoS One. 2010;5.
83. Dentchev T, Milam AH, Lee VM, Trojanowski JQ, Dunaief JL. Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. Mol Vis. 2003;9:184-190.
84. Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, Anderson DH. 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. 2002;99:11830-11835.
85. Yoshida T, Ohno-Matsui K, Ichinose S, et al. The potential role of amyloid beta in the pathogenesis of age-related macular degeneration. J Clin Invest. 2005;115:2793-2800.
86. Souied EH, Benlian P, Amouyel P, et al. The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol. 1998;125:353-359.
87. Schmidt S, Klaver C, Saunders A, et al. A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy. Ophthalmic Genet. 2002;23:209-223.
88. Chartier-Harlin MC, Parfitt M, Legrain S, et al. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet. 1994;3: 569-574.
89. Kuusisto J, Koivisto K, Kervinen K, et al. Association of apolipoprotein E phenotypes with late onset Alzheimer's disease: population based study. BMJ. 1994;309:636-638.
90. Corder EH, Saunders AM, Risch NJ, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7:180-184.
91. Wong TY, Shankar A, Klein R, et al. Apolipoprotein E gene and early age-related maculopathy: the Atherosclerosis Risk in Communities Study. Ophthalmology. 2006;113:255-259.
92. Anderson DH, Radeke MJ, Gallo NB, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res. 2010;29:95-112.
93. Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and agerelated macular degeneration. Science. 2005;308:421-424.
94. Johnson LV, Leitner WP, Staples MK, Anderson DH. Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res. 2001;73:887-896.
95. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 2000;14:835-846.
96. Umeda S, Suzuki MT, Okamoto H, et al. Molecular composition of drusen and possible involvement of anti-retinal autoimmunity in two different forms of macular degeneration in cynomolgus monkey (Macaca fascicularis). FASEB J. 2005; 19:1683-1685.
97. Eikelenboom P, Stam FC. Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol. 1982;57:239-242.
98. Shen Y, Sullivan T, Lee CM, Meri S, Shiosaki K, Lin CW. Induced expression of neuronal membrane attack complex and cell death by Alzheimer's beta-amyloid peptide. Brain Res. 1998;796:187-197.
99. Strohmeyer R, Shen Y, Rogers J. Detection of complement alternative pathway mRNA and proteins in the Alzheimer's disease brain. Brain Res Mol Brain Res. 2000;81:7-18.
100. Yasojima K, Schwab C, McGeer EG, McGeer PL. Up-regulated production and activation of the complement system in Alzheimer's disease brain. Am J Pathol. 1999;154:927-936.
101. Hamilton G, Proitsi P, Williams J, et al. Complement factor H Y402H polymorphism is not associated with late-onset Alzheimer's disease. Neuromolecular Med. 2007;9:331-334.
102. Le Fur I, Laumet G, Richard F, et al. Association study of the CFH Y402H polymorphism with Alzheimer's disease. Neurobiol Aging. 2010;31:165-166.
103. Zetterberg M, Landgren S, Andersson ME, et al. Association of complement factor H Y402H gene polymorphism with Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:720-726.
104. Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 2000;45:115-134.
105. Khandhadia S, Lotery A. Oxidation and age-related macular degeneration: insights from molecular biology. Expert Rev Mol Med. 2010;12:e34.
106. Roberts BR, Ryan TM, Bush AI, Masters CL, Duce JA. The role of metallobiology and amyloid-beta peptides in Alzheimer's disease. J Neurochem. 2012;120(suppl 1):S149-S166.
107. Danesh-Meyer HV, Birch H, Ku JY, Carroll S, Gamble G. Reduction of optic nerve fibers in patients with Alzheimer disease identified by laser imaging. Neurology. 2006;67: 1852-1854.
108. Tsai CS, Ritch R, Schwartz B, et al. Optic nerve head and nerve fiber layer in Alzheimer's disease. Arch Ophthalmol. 1991;109:199-204.
109. Moschos MM, Markopoulos I, Chatziralli I, et al. Structural and functional impairment of the retina and optic nerve in Alzheimer's disease. Curr Alzheimer Res. 2012;9:782-788.
110. Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, et al. Identification of amyloid plaques in retinas from Alzheimer's patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage. 2011;54(suppl 1): S204-S217.
111. Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem. 2007;102:1095-1104.
112. Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005;280:5892-5901.
113. Koronyo Y, Salumbides BC, Black KL, Koronyo-Hamaoui M. Alzheimer's disease in the retina: imaging retinal aβ plaques for early diagnosis and therapy assessment. Neurodegener Dis. 2012;10:285-293.
114. Allen SJ, Watson JJ, Dawbarn D. The neurotrophins and their role in Alzheimer's disease. Curr Neuropharmacol. 2011;9: 559-573.
115. Ji JZ, Elyaman W, Yip HK, et al. CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway. Eur J Neurosci. 2004;19:265-272.
116. Pease ME, Zack DJ, Berlinicke C, et al. Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Invest Ophthalmol Vis Sci. 2009;50:2194-2200.
117. Cayouette M, Behn D, Sendtner M, Lachapelle P, Gravel C. Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse. J Neurosci. 1998;18:9282-9293.
118. LaVail MM, Unoki K, Yasumura D, Matthes MT, Yancopoulos GD, Steinberg RH. Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc Natl Acad Sci U S A. 1992;89: 11249-11253.
119. Tao W, Wen R, Goddard MB, et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2002;43:3292-3298.
120. Zhang K, Hopkins JJ, Heier JS, et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci U S A. 2011;108:6241-6245.
121. Garcia P, Youssef I, Utvik JK, et al. Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer's disease. J Neurosci. 2010;30:7516-7527.
122. Ferrer I, Marin C, Rey MJ, et al. BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies. J Neuropathol Exp Neurol. 1999; 58:729-739.
123. Garzon D, Yu G, Fahnestock M. A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer's disease parietal cortex. J Neurochem. 2002;82:1058-1064.
124. Nagahara AH, Merrill DA, Coppola G, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med. 2009;15: 331-337.
125. Cheng L, Sapieha P, Kittlerova P, Hauswirth WW, Di Polo A. TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo. J Neurosci. 2002;22:3977-3986.
126. Di Polo A, Aigner LJ, Dunn RJ, Bray GM, Aguayo AJ. Prolonged delivery of brain-derived neurotrophic factor by adenovirusinfected Muller cells temporarily rescues injured retinal ganglion cells. Proc Natl Acad Sci U S A. 1998;95:3978-3983.
127. Hu Y, Cho S, Goldberg JL. Neurotrophic effect of a novel TrkB agonist on retinal ganglion cells. Invest Ophthalmol Vis Sci. 2010;51:1747-1754.
128. Mansour-Robaey S, Clarke DB, Wang YC, Bray GM, Aguayo AJ. Effects of ocular injury and administration of brainderived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A. 1994;91:1632-1636.
129. Massa SM, Yang T, Xie Y, et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest. 2010;120:1774-1785.
130. Bordji K, Becerril-Ortega J, Buisson A. Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer's disease. Rev Neurosci. 2011;22:285-294.
131. Lukiw WJ. Amyloid beta (Aβ) peptide modulators and other current treatment strategies for Alzheimer's disease (AD) [published online ahead of print March 23, 2012]. Expert Opin Emerg Drugs.
132. Iliffe S. The National Institute for Health and Clinical Excellence (NICE) and drug treatment for Alzheimer's disease. CNS Drugs. 2007;21:177-184.
133. Mount C, Downton C. Alzheimer disease: progress or profit? Nat Med. 2006;12:780-784.
134. Hare W, WoldeMussie E, Lai R, et al. Efficacy and safety of memantine, an NMDA-type open-channel blocker, for reduction of retinal injury associated with experimental glaucoma in rat and monkey. Surv Ophthalmol. 2001;45(suppl 3): S284-S289; discussion S295-S296.
135. Seki M, Lipton SA. Targeting excitotoxic/free radical signaling pathways for therapeutic intervention in glaucoma. Prog Brain Res. 2008;173:495-510.
136. Quigley HA. Clinical trials for glaucoma neuroprotection are not impossible. Curr Opin Ophthalmol. 2012;23:144-154.
137. Ding JD, Johnson LV, Herrmann R, et al. 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. 2011;108:E279-E287.
138. Ma W, Zhao L, Fontainhas AM, Fariss RN, Wong WT. Microglia in the mouse retina alter the structure and function of retinal pigmented epithelial cells: a potential cellular interaction relevant to AMD. PLoS One. 2009;4:e7945.
139. Hashimoto K. Can minocycline prevent the onset of Alzheimer's disease? Ann Neurol. 2011;69:739; author reply 739-740.
140. Parachikova A, Vasilevko V, Cribbs DH, LaFerla FM, Green KN. Reductions in amyloid-beta-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation. J Alzheimers Dis. 2010;21: 527-542.
141. Baptiste DC, Powell KJ, Jollimore CA, et al. Effects of minocycline and tetracycline on retinal ganglion cell survival after axotomy. Neuroscience. 2005;134:575-582.
142. Shimazawa M, Yamashima T, Agarwal N, Hara H. Neuroprotective effects of minocycline against in vitro and in vivo retinal ganglion cell damage. Brain Res. 2005;1053:185-194.
143. Bosco A, Inman DM, Steele MR, et al. Reduced retina microglial activation and improved optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci. 2008;49:1437-1446.
144. Butovsky O, Koronyo-Hamaoui M, Kunis G, et al. Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A. 2006;103:11784-11789.
145. Landa G, Butovsky O, Shoshani J, Schwartz M, Pollack A. Weekly vaccination with Copaxone (glatiramer acetate) as a potential therapy for dry age-related macular degeneration. Curr Eye Res. 2008;33:1011-1013.
146. Bakalash S, Ben-Shlomo G, Aloni E, et al. T-cell-based vaccination for morphological and functional neuroprotection in a rat model of chronically elevated intraocular pressure. J Mol Med (Berl). 2005;83:904-916.
147. Bakalash S, Pham M, Koronyo Y, et al. Egr1 expression is induced following glatiramer acetate immunotherapy in rodent models of glaucoma and Alzheimer's disease. Invest Ophthalmol Vis Sci. 2011;52:9033-9046.
148. Damico FM, Gasparin F, Scolari MR, Pedral LS, Takahashi BS. New approaches and potential treatments for dry age-related macular degeneration. Arq Bras Oftalmol. 2012;75:71-76.
149. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.
150. Kang JH, Pasquale LR, Willett W, et al. Antioxidant intake and primary open-angle glaucoma: a prospective study. Am J Epidemiol. 2003;158:337-346.
151. Wilkinson JT, Fraunfelder FW. Use of herbal medicines and nutritional supplements in ocular disorders: an evidencebased review. Drugs. 2011;71:2421-2434.
152. Caprioli J, Munemasa Y, Kwong JM, Piri N. Overexpression of thioredoxins 1 and 2 increases retinal ganglion cell survival after pharmacologically induced oxidative stress, optic nerve transection, and in experimental glaucoma. Trans Am Ophthalmol Soc. 2009;107:161-165.
153. Almasieh M, Lieven CJ, Levin LA, Di Polo A. A cell-permeable phosphine-borane complex delays retinal ganglion cell death after axonal injury through activation of the pro-survival extracellular signal-regulated kinases 1/2 pathway. J Neurochem. 2011;118:1075-1086.
154. Castellani RJ, Moreira PI, Perry G, Zhu X. The role of iron as a mediator of oxidative stress in Alzheimer disease. Biofactors. 2012;38:133-138.
155. Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A. 1997;94:9866-9868.
156. Kruck TP, Cui JG, Percy ME, Lukiw WJ. Molecular shuttle chelation: the use of ascorbate, desferrioxamine and Feralex-G in combination to remove nuclear bound aluminum. Cell Mol Neurobiol. 2004;24:443-459.
157. McLachlan DR, Kruck TP, Lukiw WJ, Krishnan SS. Would decreased aluminum ingestion reduce the incidence of Alzheimer's disease? CMAJ. 1991;145:793-804.
158. Ritchie CW, Bush AI, Mackinnon A, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003;60: 1685-1691.
159. Baker ML, Wang JJ, Rogers S, et al. Early age-related macular degeneration, cognitive function, and dementia: the Cardiovascular Health Study. Arch Ophthalmol. 2009;127:667-673.
160. Mattapallil MJ, Wawrousek EF, Chan CC, et al. The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. Invest Ophthalmol Vis Sci. 2012;53:2921-2927.
161. Song Y, Wei EQ, Zhang WP, et al. Minocycline protects PC12 cells against NMDA-induced injury via inhibiting 5-lipoxygenase activation. Brain Res. 2006;1085:57-67.