Drusen Deposits Associated with Aging and Age-related Macular Degeneration Contain Nonfibrillar Amyloid Oligomers

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2006 Feb 3

PMID 16453022

Citations 98

Authors

Volker Luibl

Jose M Isas

Rakez Kayed

Charles G Glabe

Ralf Langen

Jeannie Chen

Affiliations

Soon will be listed here.

Abstract

Protein misfolding and aggregation are thought to underlie the pathogenesis of many amyloid diseases, such as Alzheimer and Parkinson diseases, whereby a stepwise protein misfolding process begins with the conversion of soluble protein monomers to prefibrillar oligomers and progresses to the formation of insoluble amyloid fibrils. Drusen are extracellular deposits found in aging eyes and in eyes afflicted with age-related macular degeneration (AMD). Recent characterizations of drusen have revealed protein components that are shared with amyloid deposits. However, characteristic amyloid fibrils have thus far not been identified in drusen. In this study, we tested the hypothesis that nonfibrillar oligomers may be a common link in amyloid diseases. Oligomers consisting of distinct amyloidogenic proteins and peptides can be detected by a recently developed antibody that is thought to recognize a common structure. Notably, oligomers exhibit cellular toxicity, which suggests that they play a role in the pathogenesis of neurodegenerative diseases. Through use of the anti-oligomer antibody, we came to observe the presence of nonfibrillar, toxic oligomers in drusen. Conversely, no reactivity was observed in age-matched control eyes without drusen. These results suggest that amyloid oligomers may be involved in drusen biogenesis and that similar protein misfolding processes may occur in AMD and amyloid diseases.

Citing Articles

Sigma-2 receptor modulator CT1812 alters key pathways and rescues retinal pigment epithelium (RPE) functional deficits associated with dry age-related macular degeneration (AMD).

Lizama B, Keeling E, Cho E, Malagise E, Knezovich N, Waybright L Sci Rep. 2025; 15(1):4256.

PMID: 39929889 PMC: 11810999. DOI: 10.1038/s41598-025-87921-9.

Inflammasome activation aggravates choroidal neovascularization.

Makin R, Apicella I, Dholkawala R, Fukuda S, Hirahara S, Hirano Y Angiogenesis. 2024; 27(4):919-929.

PMID: 39316206 PMC: 11563918. DOI: 10.1007/s10456-024-09949-1.

Clinical Characteristics of Unilateral Macular Neovascularization Patients with Pachydrusen in the Fellow Eye.

Kamao H, Mitsui E, Date Y, Goto K, Mizukawa K, Miki A J Clin Med. 2024; 13(13).

PMID: 38999321 PMC: 11242765. DOI: 10.3390/jcm13133757.

Identification of highly potent and selective HTRA1 inhibitors.

Dennis D, Sun Y, Parsons D, Mahajan V, Smith M Bioorg Med Chem Lett. 2024; 109:129814.

PMID: 38815872 PMC: 11214877. DOI: 10.1016/j.bmcl.2024.129814.

Solid-state NMR MAS CryoProbe enables structural studies of human blood protein vitronectin bound to hydroxyapatite.

Gopinath T, Shin K, Tian Y, Im W, Struppe J, Perrone B J Struct Biol. 2024; 216(1):108061.

PMID: 38185342 PMC: 10939839. DOI: 10.1016/j.jsb.2024.108061.

References

Hageman G, Mullins R, Russell S, JOHNSON L, Anderson D . Vitronectin is a constituent of ocular drusen and the vitronectin gene is expressed in human retinal pigmented epithelial cells. FASEB J. 1999; 13(3):477-84. DOI: 10.1096/fasebj.13.3.477. View

Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A . Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem. 1999; 274(10):6483-92. DOI: 10.1074/jbc.274.10.6483. View

Abdelsalam A, Del Priore L, Zarbin M . Drusen in age-related macular degeneration: pathogenesis, natural course, and laser photocoagulation-induced regression. Surv Ophthalmol. 1999; 44(1):1-29. DOI: 10.1016/s0039-6257(99)00072-7. View

LeVine 3rd H . Quantification of beta-sheet amyloid fibril structures with thioflavin T. Methods Enzymol. 1999; 309:274-84. DOI: 10.1016/s0076-6879(99)09020-5. View

Kayed R, Sokolov Y, Edmonds B, McIntire T, Milton S, Hall J . Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem. 2004; 279(45):46363-6. DOI: 10.1074/jbc.C400260200. View

LeVine 3rd H . Alzheimer's beta-peptide oligomer formation at physiologic concentrations. Anal Biochem. 2004; 335(1):81-90. DOI: 10.1016/j.ab.2004.08.014. View

Krebs M, Bromley E, Donald A . The binding of thioflavin-T to amyloid fibrils: localisation and implications. J Struct Biol. 2005; 149(1):30-7. DOI: 10.1016/j.jsb.2004.08.002. View

Haines J, Hauser M, Schmidt S, Scott W, Olson L, Gallins P . Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005; 308(5720):419-21. DOI: 10.1126/science.1110359. View

Edwards A, Ritter 3rd R, Abel K, Manning A, Panhuysen C, Farrer L . Complement factor H polymorphism and age-related macular degeneration. Science. 2005; 308(5720):421-4. DOI: 10.1126/science.1110189. View

10.

Klein R, Zeiss C, Chew E, Tsai J, Sackler R, Haynes C . Complement factor H polymorphism in age-related macular degeneration. Science. 2005; 308(5720):385-9. PMC: 1512523. DOI: 10.1126/science.1109557. View

11.

Hageman G, Anderson D, Johnson L, Hancox L, Taiber A, Hardisty L . A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005; 102(20):7227-32. PMC: 1088171. DOI: 10.1073/pnas.0501536102. View

12.

Cecchi C, Baglioni S, Fiorillo C, Pensalfini A, Liguri G, Nosi D . Insights into the molecular basis of the differing susceptibility of varying cell types to the toxicity of amyloid aggregates. J Cell Sci. 2005; 118(Pt 15):3459-70. DOI: 10.1242/jcs.02473. View

13.

Malek G, JOHNSON L, Mace B, Saloupis P, Schmechel D, Rickman D . Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration. Proc Natl Acad Sci U S A. 2005; 102(33):11900-5. PMC: 1187976. DOI: 10.1073/pnas.0503015102. View

14.

Caughey B, Lansbury P . Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003; 26:267-98. DOI: 10.1146/annurev.neuro.26.010302.081142. View

15.

Mullins R, Hageman G . Human ocular drusen possess novel core domains with a distinct carbohydrate composition. J Histochem Cytochem. 1999; 47(12):1533-40. DOI: 10.1177/002215549904701205. View

16.

Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A . Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science. 2000; 287(5456):1265-9. DOI: 10.1126/science.287.5456.1265. View

17.

Mullins R, Russell S, Anderson D, Hageman G . 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(7):835-46. View

18.

Mucke L, Masliah E, Yu G, Mallory M, Rockenstein E, Tatsuno G . High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000; 20(11):4050-8. PMC: 6772621. View

19.

Klein W, Krafft G, Finch C . Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?. Trends Neurosci. 2001; 24(4):219-24. DOI: 10.1016/s0166-2236(00)01749-5. View

20.

Hageman G, Luthert P, Chong N, JOHNSON L, Anderson D, Mullins R . 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(6):705-32. DOI: 10.1016/s1350-9462(01)00010-6. View