Complement component C3 plays a critical role in protecting the aging retina in a murine model of age-related macular degeneration.
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The findings suggest that strategies that inhibit C3 in AMD may be deleterious, and both uncontrolled C3 activation and complete absence of C3 (CFH(-/-) and C3(-/-)) negatively affect aged retinas.Abstract:
Complement component C3 is the central complement component and a key inflammatory protein activated in age-related macular degeneration (AMD). AMD is associated with genetic variation in complement proteins that results in enhanced activation of C3 through the complement alternative pathway. These include complement factor H (CFH), a negative regulator of C3 activation. Both C3 inhibition and/or CFH augmentation are potential therapeutic strategies in AMD. Herein, we examined retinal integrity in aged (12 months) mice deficient in both factors H and C3 (CFH(-/-).C3(-/-)), CFH alone (CFH(-/-)), or C3 alone (C3(-/-)), and wild-type mice (C57BL/6). Retinal function was assessed by electroretinography, and retinal morphological features were analyzed at light and electron microscope levels. Retinas were also stained for amyloid β (Aβ) deposition, inflammation, and macrophage accumulation. Contrary to expectation, electroretinograms of CFH(-/-).C3(-/-) mice displayed more severely reduced responses than those of other mice. All mutant strains showed significant photoreceptor loss and thickening of Bruch's membrane compared with wild-type C57BL/6, but these changes were greater in CFH(-/-).C3(-/-) mice. CFH(-/-).C3(-/-) mice had significantly more Aβ on Bruch's membrane, fewer macrophages, and high levels of retinal inflammation than the other groups. Our data show that both uncontrolled C3 activation (CFH(-/-)) and complete absence of C3 (CFH(-/-).C3(-/-) and C3(-/-)) negatively affect aged retinas. These findings suggest that strategies that inhibit C3 in AMD may be deleterious.read more
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Journal ArticleDOI
Regulation of age-related macular degeneration-like pathology by complement factor H
TL;DR: It is demonstrated that advanced age, high-fat diet, and decreased CFH induce sub-RPE deposit formation leading to complement activation, which contributes to RPE damage and visual function impairment, which provides an improved foundation for the development of targeted therapies for AMD.
Journal ArticleDOI
Progression of Geographic Atrophy in Age-related Macular Degeneration: AREDS2 Report Number 16.
Tiarnan D L Keenan,Elvira Agrón,Amitha Domalpally,Traci E. Clemons,Freekje van Asten,Wai T. Wong,Ronald G. Danis,Srinivas R. Sadda,Philip J. Rosenfeld,Michael L. Klein,Rinki Ratnapriya,Anand Swaroop,Frederick L. Ferris,Emily Y. Chew,John Paul SanGiovanni,Traci E Clemons,Anne S. Lindblad,Robert Lindblad,Nilay Shah,Robert D. Sperduto,Wendy McBee,Gary Gensler,Molly Harrington,A. K. Henning,Katrina Jones,Kumar Thotapally,Diana Tull,Valerie Watson,Kayla Williams,Christina Gentry,F. Kaufman,Chris Morrison,Elizabeth Saverino,Sherrie Schenning,Barbara Blodi,Ronald P. Danis,Matthew D. Davis,Kathy Glander,Gregory Guilfoil,Larry D. Hubbard,Kristine A. Johnson,Ronald Klein,Barbara Nardi,Michael W. Neider,Nancy Robinson,Eileen Rosensteel,Hugh D. Wabers,Grace Zhang,Alan J. Ruby,Antonio Capone,Bawa Dass,Kimberly A. Drenser,Bruce R. Garretson,Tarek S Hassan,Michael T. Trese,George A. Williams,Jeremy D. Wolfe,Tina L. Bell,Mary Zajechowski,Dennis Bezaire,F. McIver,Anthony Medina,Jackie Pagett,Stephanie Hatch Smith,Lynn Swartz,Tom Treuter,Andrew N. Antoszyk,Justin C. Brown,David J. Browning,Walter W. Holland,Angella S. Karow,Kelly Stalford,Angela K. Price,Sarah Ennis,Sherry Fredenberg,Jenna Herby,Uma M. Balasubramaniam,Loraine Clark,Donna McClain,Michael D. McOwen,Lynn Watson,Michael L. Klein,Steven T. Bailey,Thomas J. Hwang,Andreas K. Lauer,J. Timothy Stout,Patty McCollum,M. Johnson,Patrick B. Rice,Ivana K. Kim,John I. Loewenstein,Joan W. Miller,Lucia Sobrin,Lucy H. Young,Jacqueline Sullivan,Patricia Houlihan,Linda Merry,Ann Marie Lane,Ursula Lord Bator,Claudia Evans,Sarah Brett,Charleen Callahan,Marcia Grillo,David I. Walsh,Kamella Lau Zimmerman,Gary E. Fish,Rajiv Anand,Lori E. Coors,Dwain G. Fuller,Rand Spencer,Robert C Wang,Karen Duignan,Sally Arceneaux,Hank Aguado,Nicholas Hesse,Michael Mackens,Brian Swan,Catherine A Cukras,Monica Dalal,Naima Jacobs-El,Catherine B. Meyerle,Benjamin P. Nicholson,Henry E. Wiley,Katherine Shimel,Angel Garced,Janice Oparah,Greg Short,Alana Temple,Babilonia Ayukawa,Guy Foster,Darryl Hayes,Dessie Koutsandreas,Roula Nashwinter,John Rowan,Michael Bono,Denise Cunningham,Marilois Palmer,Alicia Zetina,David H. Orth,K.A. Rezaei,J. Civantos,Sohail Hasan,Kirk H. Packo,Celeste Figliulo,Pam Stanberry,Tara Farmer,Kiersten Nelson,Shannya Townsend-Patrick,Philip J. Rosenfeld,Royce W.S. Chen,Rishi R. Doshi,Sander R. Dubovy,Brian T. Kim,Matthew D. Lowrance,Andrew A. Moshfeghi,Zayna Nahas,Gary Schienbaum,John Vishak,Christina Y. Weng,Zohar Yehoshua,Belen Rodriguez,Jose Rebimbas,Jane Gleichauf,Mike Kicak,Jason Mena,Tim Odem,Elizabeth Sferza-Camp,Alicia Disgdiertt,Jim Oramas,Isabel Rams,Stephanie Thatcher,Susan B. Bressler,Neil M. Bressler,Daniel Finkelstein,Steven H. Sherman,Sharon D. Solomon,Howard S. Ying,Rita Denbow,Deborah A. Phillips,Elizabeth Radcliffe,Judy Belt,Dennis Cain,David Emmert,Mark Herring,Jacquelyn McDonald,G. Baker Hubbard,Chris S. 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Pulido,Diane Vogen,Rebecca Nielsen,Karin Berg,Jean Burrington,Shannon Howard,Joan Overend,Zbigniew Krason,Denise Lewison,Thomas M. Link,Kevin J. Blinder,Nicholas E. Engelbrecht,M. Gilbert Grand,Daniel P. Joseph,Gaurav K. Shah,Bradley T. Smith,Matthew A. Thomas,Rhonda Weeks,Lynda Boyd,Dana Gabel,Ron A. Adelman,John J Huang,James Kempton,Aaron J. Parnes,Jennifer Dupont,Elizabeth Perotti,Victoria Donaldson,Kenneth Fong,Pamela Ossorio,Anita Agarwal,Paul Sternberg,Sandy Owings,T. Adkins,Elaine Lok,Garvin Munn,Buddy Skellie,Neelakshi Bhagat,Monique S. Roy,Marco A. Zarbin,Catherine Fay,Michael Lazar,Beth Malpica,Tatiana Mikheyav,Lawrence Ulanski,Jennifer I. Lim,Marcia Niec,Tametha Johnson,Yesenia Ovando,Catherine Nail Carroll,Mark Janowicz,Steven D. Schwartz,David Cupp,Michael B. Gorin,Gad Heilweil,Hamid Hosseini,Jean-Pierre Hubschman,Allan E. Kreiger,Tara Young McCannel,Carolyn K. 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Yannuzzi,Maria Scolaro,Eugene Agresta,Nancy Gonzalez,Sandeep Grover,Kakarla V. Chalam,Shailesh K Gupta,Christopher J. Lyons,Wenhua Li,Chirag Patel,Jose Carrion,Henry Ferreyra,Amberly Rodriguez,Iliana Molina,Gabriel Balea,Pam Emory,Marlene Rico,Giorgio Siqueiros,Alexander J. Brucker,Joshua L. Dunaief,Juan E. Grunwald,Benjamin J. Kim,Albert M. Maguire,Brian L VanderBeek,Sheri Drossner,Joan DuPont,Rebecca Salvo,James Berger,Cheryl Devine,Bill Nyberg,Laurel Weeney,David A. DiLoreto,Mina M. Chung,Valerie Davis,Peter MacDowell,George O. Gara,Daniel Castillo,Andrea Czubinski,Melissa Keim,Brandi Hardy,Rachel Grunhaus Hollar,Lynn Schueckler,Alice T. Lyon,Aaron Weinberg,Mira Shiloach,Nicole Pelkofer,Qin Zhou,Laura McPoland,Rajendra S. Apte,P. Kumar Rao,Sam Pistorius,Jamie Kambarian,Eve Adcock,Sarah Gould,Melanie Quinn,Rhonda Curtis,Amy Frost,Charla Meyer,Greg Rathert +1001 more
TL;DR: GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss, and the genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA.
Journal ArticleDOI
VEGF regulates local inhibitory complement proteins in the eye and kidney
Lindsay S. Keir,Rachel Firth,Lyndsey Aponik,Daniel Feitelberg,Susumu Sakimoto,Edith Aguilar,Gavin I. Welsh,Anna Richards,Yoshihiko Usui,Simon C. Satchell,Valeryia Kuzmuk,Richard J M Coward,Jonathan Goult,Katherine R. Bull,Ruchi Sharma,Kapil Bharti,Peter D. Westenskow,Iacovos P. Michael,Moin A. Saleem,Martin Friedlander +19 more
TL;DR: Results suggest that VEGF protects the retinal and glomerular microvasculature, not only through VEGFR2-mediated vasculotrophism, but also through modulation of local complement proteins that could protect against complement-mediated damage.
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Complement factor H in AMD: Bridging genetic associations and pathobiology.
TL;DR: A model in which CFH H402 affects CFH binding to heparan sulfate proteoglycans leading to accelerated lipoprotein accumulation in BrM and drusen progression is proposed, based on the group's studies.
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Recharging mitochondrial batteries in old eyes. Near infra-red increases ATP.
Despoina Gkotsi,Rana Begum,Thomas E. Salt,Gerassimos Lascaratos,Chris Hogg,Kai-Yin Chau,Anthony H.V. Schapira,Glen Jeffery +7 more
TL;DR: This is the first demonstration of ATP manipulation in vivo and may provide a simple non-invasive route to combating age related tissue decline.
References
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Complement Factor H Polymorphism in Age-Related Macular Degeneration
Robert J. Klein,Caroline J. Zeiss,Emily Y. Chew,Jen-yue Tsai,Richard S. Sackler,Chad Haynes,A. K. Henning,John Paul SanGiovanni,Shrikant Mane,Susan T. Mayne,Michael B. Bracken,Frederick L. Ferris,Jurg Ott,Colin J. Barnstable,Josephine Hoh +14 more
TL;DR: A genome-wide screen for polymorphisms associated with age-related macular degeneration revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402 in the complement factor H gene.
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A specific amyloid-|[beta]| protein assembly in the brain impairs memory
Sylvain Lesné,Ming Teng Koh,Linda Kotilinek,Rakez Kayed,Charles G. Glabe,Austin J. Yang,Michela Gallagher,Karen H. Ashe +7 more
TL;DR: It is found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-β assembly, which is proposed to be Aβ*56 (Aβ star 56), which may contribute to cognitive deficits associated with Alzheimer's disease.
Journal ArticleDOI
Complement factor H variant increases the risk of age-related macular degeneration.
Jonathan L. Haines,Michael A. Hauser,Silke Schmidt,William K. Scott,Lana M. Olson,Paul Gallins,Kylee L. Spencer,Shu Ying Kwan,Maher A. Noureddine,John R. Gilbert,Nathalie Schnetz-Boutaud,Anita Agarwal,Eric A. Postel,Margaret A. Pericak-Vance +13 more
TL;DR: DNA resequencing of the complement factor H gene within this haplotype revealed a common coding variant that significantly increases the risk for AMD with odds ratios between 2.45 and 5.57, which likely explains ∼43% of AMD in older adults.
Journal ArticleDOI
Complement Factor H Polymorphism and Age-Related Macular Degeneration
Albert O. Edwards,Robert C. Ritter,Kenneth Abel,Alisa K. Manning,Carolien I.M. Panhuysen,Lindsay A. Farrer +5 more
TL;DR: In this paper, single-nucleotide polymorphisms were tested for association with AMD in two independent case-control populations and significant association was identified within the regulation of complement activation locus and was centered over a tyrosine-402 --> histidine-402 protein polymorphism in the gene encoding complement factor.
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