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Beta-amyloid sequelae in the eye: a critical review on its diagnostic significance and clinical relevance in Alzheimer’s disease

Molecular Psychiatry volume 22, pages 353–363 (2017)Cite this article

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Abstract

Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder. There is no test for its definitive diagnosis in routine clinical practice. Although phase III clinical trials have failed, only symptomatic treatment is currently available; a possible reason for these failed trials is that intervention commenced at an advanced stage of the disease. The hallmarks of an AD brain include plaques comprising of extracellular beta-amyloid (Aβ) protein aggregates and intracellular hyperphosphorylated neurofibrillary tangles of tau. Research into the preclinical diagnosis of AD has provided considerable evidence regarding early neuropathological changes using brain Aβ imaging and the cerebrospinal fluid biomarkers, Aβ and tau. Both these approaches have limitations that are expensive, invasive or time consuming and thus preclude them from screening at-risk population. Recent studies have demonstrated the presence of Aβ plaques in the eyes of AD subjects, which is positively associated with their brain Aβ burden. Thus ocular biomarkers point to a potential avenue for an earlier, relatively low-cost diagnosis in order for therapeutic interventions to be effective. Here we review the literature that spans the investigation for the presence of Aβ in aging eyes and the significance of its deposition in relation to AD pathology. We discuss clinical studies investigating in vivo imaging of Aβ in the eye and its association with brain Aβ burden and therapies that target ocular Aβ. Finally, we focus on the need to characterize AD-specific retinal Aβ to differentiate Aβ found in some eye diseases. Based on the current evidence, we conclude that integration of ocular biomarkers that can correctly predict brain Aβ burden would have an important role as a non-invasive, yet economical surrogate marker in the diagnostic process of AD.

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References

  1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . Clinical diagnosis of Alzheimer's disease Report of the NINCDS‐ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34: 939–944.

    Article  CAS  PubMed  Google Scholar 

  2. Price JL, Morris JC . Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol 1999; 45: 358–368.

    Article  CAS  PubMed  Google Scholar 

  3. Petersen RC, Wiste HJ, Weigand SD, Rocca WA, Roberts RO, Mielke MM et al. Association of elevated amyloid levels with cognition and biomarkers in cognitively normal people from the community. JAMA Neurol 2016; 73: 85–92.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol 2013; 12: 357–367.

    Article  CAS  PubMed  Google Scholar 

  5. Rowe CC, Bourgeat P, Ellis KA, Brown B, Lim YY, Mulligan R et al. Predicting Alzheimer disease with β‐amyloid imaging: Results from the Australian imaging, biomarkers, and lifestyle study of ageing. Ann Neurol 2013; 74: 905–913.

    Article  CAS  PubMed  Google Scholar 

  6. Sernagor E, Eglen SJ, Wong RO . Development of retinal ganglion cell structure and function. Prog Retin Eye Res 2001; 20: 139–174.

    Article  CAS  PubMed  Google Scholar 

  7. Cooper LS, Wong TY, Klein R, Sharrett AR, Bryan RN, Hubbard LD et al. Retinal microvascular abnormalities and MRI-defined subclinical cerebral infarction the atherosclerosis risk in communities study. Stroke 2006; 37: 82–86.

    Article  PubMed  Google Scholar 

  8. London A, Benhar I, Schwartz M . The retina as a window to the brain—from eye research to CNS disorders. Nat Rev Neurol 2012; 9: 44–53.

    Article  CAS  PubMed  Google Scholar 

  9. Kaur C, Foulds W, Ling E . Blood–retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res 2008; 27: 622–647.

    Article  CAS  PubMed  Google Scholar 

  10. Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller CA, Ko MK, Black KL 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: S204–S217.

    Article  CAS  PubMed  Google Scholar 

  11. Goldstein LE, Muffat JA, Cherny RA, Moir RD, Ericsson MH, Huang X et al. Cytosolic β-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease. Lancet 2003; 361: 1258–1265.

    Article  CAS  PubMed  Google Scholar 

  12. Kerbage C, Sadowsky CH, Tariot PN, Agronin M, Alva G, Turner FD et al. Detection of amyloid beta signature in the lens and its correlation in the brain to aid in the diagnosis of Alzheimer's disease. Am J Alzheimers Dis Other Demen 2015; 30: 738–745.

    Article  PubMed  Google Scholar 

  13. La Morgia C, Ross-Cisneros FN, Koronyo Y, Hannibal J, Gallassi R, Cantalupo G et al. Melanopsin retinal ganglion cell loss in Alzheimer disease. Ann Neurol 2016; 79: 90–109.

    Article  CAS  PubMed  Google Scholar 

  14. Frederikse PH . Amyloid-like protein structure in mammalian ocular lenses. Curr Eye Res 2000; 20: 462–468.

    Article  CAS  PubMed  Google Scholar 

  15. Frederikse PH, Garland D, Zigler JS Jr., Piatigorsky J . Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta has toxic effects on lens epithelial cells. J Biol Chem 1996; 271: 10169–10174.

    Article  CAS  PubMed  Google Scholar 

  16. Frederikse PH, Zigler JS Jr . Presenilin expression in the ocular lens. Curr Eye Res 1998; 17: 947–952.

    Article  CAS  PubMed  Google Scholar 

  17. Li G, Percontino L, Sun Q, Qazi AS, Frederikse PH . Beta-amyloid secretases and beta-amloid degrading enzyme expression in lens. Mol Vis 2003; 9: 179–183.

    CAS  PubMed  Google Scholar 

  18. Morin PJ, Abraham CR, Amaratunga A, Johnson RJ, Huber G, Sandell JH et al. Amyloid precursor protein is synthesized by retinal ganglion cells, rapidly transported to the optic nerve plasma membrane and nerve terminals, and metabolized. J Neurochem 1993; 61: 464–473.

    Article  CAS  PubMed  Google Scholar 

  19. Ho T, Vessey KA, Cappai R, Dinet V, Mascarelli F, Ciccotosto GD et al. Amyloid precursor protein is required for normal function of the rod and cone pathways in the mouse retina. PLoS One 2012; 7: e29892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Prakasam A, Muthuswamy A, Ablonczy Z, Greig NH, Fauq A, Rao KJ et al. Differential accumulation of secreted AβPP metabolites in ocular fluids. J Alzheimers Dis 2010; 20: 1243–1253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kam JH, 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: e13127.

    Article  CAS  Google Scholar 

  22. Kam JH, Lynch A, Begum R, Cunea A, Jeffery G . Topical cyclodextrin reduces amyloid beta and inflammation improving retinal function in ageing mice. Exp Eye Res 2015; 135: 59–66.

    Article  CAS  Google Scholar 

  23. Lee V, Rekhi E, Hoh Kam J, Jeffery G . Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function. Neurobiol Aging 2012; 33: 2382–2389.

    Article  CAS  PubMed  Google Scholar 

  24. Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 2006; 440: 352–357.

    Article  CAS  PubMed  Google Scholar 

  25. Goldblum D, Kipfer-Kauer A, Sarra G-M, Wolf S, Frueh BE . Distribution of amyloid precursor protein and amyloid-β immunoreactivity in DBA/2J glaucomatous mouse retinas. Invest Ophthalmol Vis Sci 2007; 48: 5085–5090.

    Article  PubMed  Google Scholar 

  26. Wang J, Ohno-Matsui K, Morita I . Elevated amyloid beta production in senescent retinal pigment epithelium, a possible mechanism of subretinal deposition of amyloid beta in age-related macular degeneration. Biochem Biophys Res Commun 2012; 423: 73–78.

    Article  CAS  PubMed  Google Scholar 

  27. Wang J, Zhu C, Xu Y, Liu B, Wang M, Wu K . Development and expression of amyloid‐β peptide 42 in retinal ganglion cells in rats. Anat Rec 2011; 294: 1401–1405.

    Article  CAS  Google Scholar 

  28. Wang J, Ohno-Matsui K, Morita I . Cholesterol enhances amyloid beta deposition in mouse retina by modulating the activities of Abeta-regulating enzymes in retinal pigment epithelial cells. Biochem Biophys Res Commun 2012; 424: 704–709.

    Article  CAS  PubMed  Google Scholar 

  29. Guo LY, Alekseev O, Li Y, Song Y, Dunaief JL . Iron increases APP translation and amyloid-beta production in the retina. Exp Eye Res 2014; 129: 31–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ayton S, Faux NG, Bush AI, ADNI. Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nat Commun 2015; 6: 6760.

    Article  CAS  PubMed  Google Scholar 

  31. Martins IJ, Hone E, Foster JK, Sunram-Lea SI, Gnjec A, Fuller SJ et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry 2006; 11: 721–736.

    Article  CAS  PubMed  Google Scholar 

  32. Löffler K, Edward DP, Tso M . Immunoreactivity against tau, amyloid precursor protein, and beta-amyloid in the human retina. Invest Ophthalmol Vis Sci 1995; 36: 24–31.

    PubMed  Google Scholar 

  33. Seth A, Cui J, To E, Kwee M, Matsubara J . Complement-associated deposits in the human retina. Invest Ophthalmol Vis Sci 2008; 49: 743–750.

    Article  PubMed  Google Scholar 

  34. Leger F, Fernagut P-O, Canron M-H, Léoni S, Vital C, Tison F et al. Protein aggregation in the aging retina. J Neuropathol Exp Neurol 2011; 70: 63–68.

    Article  CAS  PubMed  Google Scholar 

  35. Parthasarathy R, Chow KM, Derafshi Z, Fautsch MP, Hetling JR, Rodgers DW et al. Reduction of amyloid-beta levels in mouse eye tissues by intra-vitreally delivered neprilysin. Exp Eye Res 2015; 138: 134–144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chen ST, Patel AJ, Garey LJ, Jen LS . Expression of beta-amyloid precursor protein immunoreactivity in the retina of the rat during normal development and after neonatal optic tract lesion. Neuroreport 1997; 8: 713–717.

    Article  CAS  PubMed  Google Scholar 

  37. Dinet V, An N, Ciccotosto GD, Bruban J, Maoui A, Bellingham SA et al. APP involvement in retinogenesis of mice. Acta Neuropathol 2011; 121: 351–363.

    Article  CAS  PubMed  Google Scholar 

  38. Plummer S, Van den Heuvel C, Thornton E, Corrigan F, Cappai R . The neuroprotective properties of the amyloid precursor protein following traumatic brain injury. Aging Dis 2016; 7: 163–179.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Cárdenas-Aguayo MdC, Silva-Lucero MdC, Cortes-Ortiz M, Jiménez-Ramos B, Gómez-Virgilio L, Ramírez-Rodríguez G et al. Physiological role of amyloid beta in neural cells: the cellular trophic activity. InTech: Rijeka, Croatia, 2014.

  40. Cunvong K, Huffmire D, Ethell DW, Cameron DJ . Amyloid-beta increases capillary bed density in the adult zebrafish retina. Invest Ophthalmol Vis Sci 2013; 54: 1516–1521.

    Article  CAS  PubMed  Google Scholar 

  41. Bruban J, Glotin A-L, Dinet V, Chalour N, Sennlaub F, Jonet L et al. Amyloid-β(1-42) alters structure and function of retinal pigmented epithelial cells. Aging Cell 2009; 8: 162–177.

    Article  CAS  PubMed  Google Scholar 

  42. Ning A, Cui J, To E, Ashe KH, Matsubara J . Amyloid-β deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Invest Ophthalmol Vis Sci 2008; 49: 5136–5143.

    Article  PubMed  Google Scholar 

  43. Perez SE, Lumayag S, Kovacs B, Mufson EJ, Xu S . β-amyloid deposition and functional impairment in the retina of the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease. Invest Ophthalmol Vis Sci 2009; 50: 793–800.

    Article  PubMed  Google Scholar 

  44. Wang J, Tanila H, Puolivali J, Kadish I, van Groen T . Gender differences in the amount and deposition of amyloidbeta in APPswe and PS1 double transgenic mice. Neurobiol Dis 2003; 14: 318–327.

    Article  CAS  PubMed  Google Scholar 

  45. Dutescu RM, Li Q-X, Crowston J, Masters CL, Baird PN, Culvenor JG . Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease. Graefes Arch Clin Exp Ophthalmol 2009; 247: 1213–1221.

    Article  CAS  PubMed  Google Scholar 

  46. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol 2015; 14: 388–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Morales I, Guzman-Martinez L, Cerda-Troncoso C, Farias GA, Maccioni RB . Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci 2014; 8: 112.

    PubMed  PubMed Central  Google Scholar 

  48. Alexandrov PN, Pogue A, Bhattacharjee S, Lukiw WJ . Retinal amyloid peptides and complement factor H in transgenic models of Alzheimer's disease. Neuroreport 2011; 22: 623–627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Edwards MM, Rodríguez JJ, Gutierrez-Lanza R, Yates J, Verkhratsky A, Lutty GA . Retinal macroglia changes in a triple transgenic mouse model of Alzheimer's disease. Exp Eye Res 2014; 127: 252–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tsai Y, Lu B, Ljubimov AV, Girman S, Ross-Cisneros FN, Sadun AA et al. Ocular changes in TgF344-AD rat model of Alzheimer's disease. Invest Ophthalmol Vis Sci 2014; 55: 523–534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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.

    PubMed  Google Scholar 

  52. McKee AC, Au R, Cabral HJ, Kowall NW, Seshadri S, Kubilus CA et al. Visual association pathology in preclinical Alzheimer disease. J Neuropathol Exp Neurol 2006; 65: 621–630.

    Article  PubMed  Google Scholar 

  53. Shimazawa M, Inokuchi Y, Okuno T, Nakajima Y, Sakaguchi G, Kato A et al. Reduced retinal function in amyloid precursor protein‐over‐expressing transgenic mice via attenuating glutamate‐N‐methyl‐d‐aspartate receptor signaling. J Neurochem 2008; 107: 279–290.

    Article  CAS  PubMed  Google Scholar 

  54. Park SW, Kim JH, Mook-Jung I, Kim K-W, Park WJ, Park KH et al. Intracellular amyloid beta alters the tight junction of retinal pigment epithelium in 5XFAD mice. Neurobiol Aging 2014; 35: 2013–2020.

    Article  CAS  PubMed  Google Scholar 

  55. Liu B, Rasool S, Yang Z, Glabe CG, Schreiber SS, Ge J et al. Amyloid-peptide vaccinations reduce β-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer’s transgenic mice. Am J Pathol 2009; 175: 2099–2110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. More SS, Vince R . Hyperspectral imaging signatures detect amyloidopathy in Alzheimer’s mouse retina well before onset of cognitive decline. ACS Chem Neurosci 2015; 6: 306–315.

    Article  CAS  PubMed  Google Scholar 

  57. Mattapallil MJ, Wawrousek EF, Chan C-C, Zhao H, Roychoudhury J, Ferguson TA 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 rd8 mutation in vendor B6 Mice and ES cells. Invest Ophthalmol Vis Sci 2012; 53: 2921–2927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Moncaster JA, Pineda R, Moir RD, Lu S, Burton MA, Ghosh JG et al. Alzheimer's disease amyloid-β links lens and brain pathology in down syndrome. PLoS One 2010; 5: e10659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kerbage C, Sadowsky CH, Jennings D, Cagle GD, Hartung PD . Alzheimer's disease diagnosis by detecting exogenous fluorescent signal of ligand bound to Beta amyloid in the lens of human eye: an exploratory study. Front Neurol 2013; 4: 62.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Frost S, Kanagasingam Y, Macaulay L, Koronyo-Hamaoui M, Koronyo Y, Biggs D et al. Retinal amyloid fluorescence imaging predicts cerebral amyloid burden and Alzheimer's disease. Alzheimers Demen 2014; 10: P234–P235.

    Article  Google Scholar 

  61. Rafii MS, Wishnek H, Brewer JB, Donohue MC, Ness S, Mobley WC et al. The down syndrome biomarker initiative (DSBI) pilot: proof of concept for deep phenotyping of Alzheimer's disease biomarkers in down syndrome. Front Behav Neurosci 2015; 9: 239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kayabasi U, Sergott R, Rispoli M . Retinal examination for the diagnosis of Alzheimer’s disease. Int J Ophthalmic Pathol 2014; 3: 4.

    Article  Google Scholar 

  63. Michael R, Rosandić J, Montenegro GA, Lobato E, Tresserra F, Barraquer RI et al. Absence of beta-amyloid in cortical cataracts of donors with and without Alzheimer's disease. Exp Eye Res 2013; 106: 5–13.

    Article  CAS  PubMed  Google Scholar 

  64. Michael R, Otto C, Lenferink A, Gelpi E, Montenegro GA, Rosandić J et al. Absence of amyloid-beta in lenses of Alzheimer patients: a confocal Raman microspectroscopic study. Exp Eye Res 2014; 119: 44–53.

    Article  CAS  PubMed  Google Scholar 

  65. Blanks JC, Hinton DR, Sadun AA, Miller CA . Retinal ganglion cell degeneration in Alzheimer's disease. Brain Res 1989; 501: 364–372.

    Article  CAS  PubMed  Google Scholar 

  66. Hinton DR, Sadun AA, Blanks JC, Miller CA . Optic-nerve degeneration in Alzheimer's disease. N Engl J Med 1986; 315: 485–487.

    Article  CAS  PubMed  Google Scholar 

  67. Ho CY, Troncoso JC, Knox D, Stark W, Eberhart CG . Beta‐amyloid, phospho‐tau and alpha‐synuclein deposits similar to those in the brain are not identified in the eyes of Alzheimer's and Parkinson's disease patients. Brain Pathol 2014; 24: 25–32.

    Article  CAS  PubMed  Google Scholar 

  68. Schön C, Hoffmann NA, Ochs SM, Burgold S, Filser S, Steinbach S et al. Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice. PLoS One 2012; 7: e53547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Guo L, Duggan J, Cordeiro M . Alzheimer's disease and retinal neurodegeneration. Curr Alzheimer Resarch 2010; 7: 3–14.

    Article  CAS  Google Scholar 

  70. Dehabadi MH, Davis BM, Wong TK, Cordeiro MF . Retinal manifestations of Alzheimer's disease. Neurodegener Dis Manag 2014; 4: 241–252.

    Article  PubMed  Google Scholar 

  71. Laude A, Lascaratos G, Henderson RD, Starr JM, Deary IJ, Dhillon B . Retinal nerve fiber layer thickness and cognitive ability in older people: the Lothian Birth Cohort 1936 study. BMC Ophthalmology 2013; 13: 28–28.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Shen Y, Shi Z, Jia R, Zhu Y, Cheng Y, Feng W et al. The attenuation of retinal nerve fiber layer thickness and cognitive deterioration. Front Cell Neurosci 2013; 7: 142.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Jackson GR, Owsley C . Visual dysfunction, neurodegenerative diseases, and aging. Neurol Clin 2003; 21: 709–728.

    Article  PubMed  Google Scholar 

  74. Javaid FZ, Brenton J, Guo L, Cordeiro MF . Visual and ocular manifestations of Alzheimer’s disease and their use as biomarkers for diagnosis and progression. Front Neurol 2016; 7: 55.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Li L, Luo J, Chen D, Tong JB, Zeng LP, Cao YQ et al. BACE1 in the retina: a sensitive biomarker for monitoring early pathological changes in Alzheimer's disease. Neural Regen Res 2016; 11: 447–453.

    Article  PubMed  PubMed Central  Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. Bitel CL, Kasinathan C, Kaswala RH, Klein WL, Frederikse PH . Amyloid-beta and tau pathology of Alzheimer's disease induced by diabetes in a rabbit animal model. J Alzheimers Dis 2012; 32: 291–305.

    Article  CAS  PubMed  Google Scholar 

  78. Nagai N, Ito Y, Tanino T . Effect of high glucose levels on amyloid beta production in retinas of spontaneous diabetes mellitus Otsuka Long-Evans Tokushima fatty rats. Biol Pharm Bull 2015; 38: 601–610.

    Article  CAS  PubMed  Google Scholar 

  79. Anderson DH, Talaga KC, Rivest AJ, Barron E, Hageman GS, Johnson LV . Characterization of β amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res 2004; 78: 243–256.

    Article  CAS  PubMed  Google Scholar 

  80. Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, Anderson DH . The Alzheimer's Aβ-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci USA 2002; 99: 11830–11835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sandilands A, Hutcheson AM, Long HA, Prescott AR, Vrensen G, Löster J et al. Altered aggregation properties of mutant γ‐crystallins cause inherited cataract. EMBO J 2002; 21: 6005–6014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ogata J, Okayama M, Goto I, Inomata H, Yoshida I, Omae T . Primary familial amyloidosis with vitreous opacities. Acta Neuropathol 1978; 42: 67–70.

    Article  CAS  PubMed  Google Scholar 

  83. Alberto R, Luigi S, Ambrogio F, Daniele D . Bilateral optic neuropathy and intraretinal deposits after pars plana vitrectomy in amyloidosis. Indian J Ophthalmol 2015; 63: 72–74.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Berlau J, Lorenz P, Beck R, Makovitzky J, Schlötzer-Schrehardt U, Thiesen H-J et al. Analysis of aqueous humour proteins of eyes with and without pseudoexfoliation syndrome. Graefes Arch Clin Exp Ophthalmol 2001; 239: 743–746.

    Article  CAS  PubMed  Google Scholar 

  85. 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.

    Article  CAS  PubMed  Google Scholar 

  86. Linke R . Congo red staining of amyloid: improvements and practical guide for a more precise diagnosis of amyloid and the different amyloidoses. In: Uversky V, Fink A (ed). Protein Misfolding, Aggregation, and Conformational Diseases. Springer: USA, 2006, p 239–276.

    Book  Google Scholar 

  87. Kennedy CJ, Rakoczy PE, Constable IJ . Lipofuscin of the retinal pigment epithelium: a review. Eye 1995; 9: 763–771.

    Article  PubMed  Google Scholar 

  88. Delori FC, Goger DG, Dorey CK . Age-related accumulation and spatial distribution of lipofuscin in RPE of normal subjects. Invest Ophthalmol Vis Sci 2001; 42: 1855–1866.

    CAS  PubMed  Google Scholar 

  89. Miller C, Krasnow J, Schwartz LH . Medical Imaging in Clinical Trials. Springer: London, UK, 2014.

    Book  Google Scholar 

  90. Young RW . Pathophysiology of age-related macular degeneration. Surv Ophthalmol 1987; 31: 291–306.

    Article  CAS  PubMed  Google Scholar 

  91. Hageman GS, Luthert PJ, Chong NV, Johnson LV, Anderson DH, Mullins RF . 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 2001; 20: 705–732.

    Article  CAS  PubMed  Google Scholar 

  92. Luibl V, Isas JM, Kayed R, Glabe CG, Langen R, Chen J . Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. J Clin Invest 2006; 116: 378–385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pauleikhoff D, Barondes M, Minassian D, Chisholm I, Bird A . Drusen as risk factors in age-related macular disease. Am J Ophthalmol 1990; 109: 38–43.

    Article  CAS  PubMed  Google Scholar 

  94. Isas JM, Luibl V, Johnson LV, Kayed R, Wetzel R, Glabe CG et al. Soluble and mature amyloid fibrils in drusen deposits. Invest Ophthalmol Vis Sci 2010; 51: 1304–1310.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Ohno-Matsui K . Parallel findings in age-related macular degeneration and Alzheimer's disease. Prog Retin Eye Res 2011; 30: 217–238.

    Article  PubMed  Google Scholar 

  96. Toops KA, Tan LX, Lakkaraju A . Apolipoprotein E isoforms and AMD. Adv Exp Med Biol 2016; 854: 3–9.

    Article  CAS  PubMed  Google Scholar 

  97. Uro-Coste E, Russano dPG, Guilbeau-Frugier C, Sastre N, Ousset P, da Silva N et al. Cerebral amyloid angiopathy and microhemorrhages after amyloid beta vaccination: case report and brief review. Clin Neuropathol 2009; 29: 209–216.

    Article  Google Scholar 

  98. Ding JD, Lin J, Mace BE, Herrmann R, Sullivan P, Bowes Rickman C . 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 2008; 48: 339–345.

    Article  CAS  PubMed  Google Scholar 

  99. Ding JD, Johnson LV, Herrmann R, Farsiu S, Smith SG, Groelle M 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 USA 2011; 108: E279–E287.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Guo L, Salt TE, Luong V, Wood N, Cheung W, Maass A et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA 2007; 104: 13444–13449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yucel YH, Gupta N, Zhang Q, Mizisin AP, Kalichman MW, Weinreb RN . Memantine protects neurons from shrinkage in the lateral geniculate nucleus in experimental glaucoma. Arch Ophthalmol 2006; 124: 217–225.

    Article  CAS  PubMed  Google Scholar 

  102. Almasieh M, Zhou Y, Kelly ME, Casanova C, Di Polo A . Structural and functional neuroprotection in glaucoma: role of galantamine-mediated activation of muscarinic acetylcholine receptors. Cell Death Dis 2010; 1: e27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yi YM, Cai L, Shao Y, Xu M, Yi JL . The protective role of tacrine and donepezil in the retina of acetylcholinesterase knockout mice. Int J Ophthalmol 2015; 8: 884–890.

    PubMed  PubMed Central  Google Scholar 

  104. Melov S, Wolf N, Strozyk D, Doctrow SR, Bush AI . Mice transgenic for Alzheimer disease beta-amyloid develop lens cataracts that are rescued by antioxidant treatment. Free Radic Biol Med 2005; 38: 258–261.

    Article  CAS  PubMed  Google Scholar 

  105. Durk MR, Han K, Chow EC, Ahrens R, Henderson JT, Fraser PE et al. 1alpha,25-Dihydroxyvitamin D3 reduces cerebral amyloid-beta accumulation and improves cognition in mouse models of Alzheimer's disease. J Neurosci 2014; 34: 7091–7101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yao J, Ho D, Calingasan NY, Pipalia NH, Lin MT, Beal MF . Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J Exp Med 2012; 209: 2501–2513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kosinski‐Collins MS, King J . In vitro unfolding, refolding, and polymerization of human γD crystallin, a protein involved in cataract formation. Protein Sci 2003; 12: 480–490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Amaro M, Wellbrock T, Birch DJ, Rolinski OJ . Inhibition of beta-amyloid aggregation by fluorescent dye labels. Appl Phys Lett 2014; 104: 063704.

    Article  CAS  Google Scholar 

  109. Woo JM, Shin DY, Lee SJ, Joe Y, Zheng M, Yim JH et al. Curcumin protects retinal pigment epithelial cells against oxidative stress via induction of heme oxygenase-1 expression and reduction of reactive oxygen. Mol Vis 2012; 18: 901–908.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Campbell MC . High Resolution Imaging of the Eye-Implications for Diagnosis and Therapy. In: Bio-Optics Design and Application, Optical Society of America, 2013 (abstract BTh2A-1).

  111. Campbell MC, Avila F, Emptage L, Kisilak M, Bueno JM . Polarimetry in ex vivo retina from donors with Alzheimer's disease. In: Frontiers in Optics, Optical Society of America, 2013 (abstract FW5F-4).

  112. Campbell MC, Chow WC, Emptage L, Cookson C, Milgram B, Dobson H . Polarization properties of amyloid beta in an animal model of Alzheimer's disease. In: Frontiers in Optics, Optical Society of America, 2014 (abstract FW5F-4).

  113. Jentsch S, Schweitzer D, Schmidtke KU, Peters S, Dawczynski J, Bar KJ et al. Retinal fluorescence lifetime imaging ophthalmoscopy measures depend on the severity of Alzheimer's disease. Acta Ophthalmol 2015; 93: e241–e247.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, WA, Australia

    T M Shah, S M Gupta & R N Martins

  2. Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Perth, WA, Australia

    T M Shah, S M Gupta & R N Martins

  3. KaRa Institute of Neurological Diseases, Macquarie Park, NSW, Australia

    P Chatterjee & R N Martins

  4. Australian School of Advanced Medicine, Faculty of Medicine and Health Sciences, Macquarie University, North Ryde, NSW, Australia

    P Chatterjee & R N Martins

  5. Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin, Ireland

    M Campbell

  6. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, WA, Australia

    R N Martins

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  1. T M Shah
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  2. S M Gupta
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  3. P Chatterjee
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  4. M Campbell
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Correspondence to R N Martins.

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Shah, T., Gupta, S., Chatterjee, P. et al. Beta-amyloid sequelae in the eye: a critical review on its diagnostic significance and clinical relevance in Alzheimer’s disease. Mol Psychiatry 22, 353–363 (2017). https://doi.org/10.1038/mp.2016.251

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  • DOI: https://doi.org/10.1038/mp.2016.251

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