A monoclonal antibody targeting amyloid β (Aβ) restores complement factor I bioactivity: Potential implications in age-related macular degeneration and Alzheimer’s disease
| Autor: | Megan M. McLaughlin, Francisco J. López, Hong Chen, Kameran Lashkari, Yong-Qing Lin, Gianna C Teague, Sanjay Kumar |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Physiology Complement System lcsh:Medicine Pharmacology Alzheimer's Disease Biochemistry Pathogenesis Macular Degeneration Immune Physiology Medicine and Health Sciences Geriatric Ophthalmology Enzyme-Linked Immunoassays lcsh:Science Enzyme Chemistry Complement Activation Immune System Proteins Multidisciplinary biology Retinal Degeneration Antibodies Monoclonal Neurodegenerative Diseases Body Fluids Blood Neurology Complement Factor I Retinal Disorders Female Health Services Research Anatomy Antibody Research Article medicine.drug_class Immunology Complement factor I Research and Analysis Methods Monoclonal antibody Blood Plasma Proinflammatory cytokine 03 medical and health sciences Alzheimer Disease Mental Health and Psychiatry medicine Humans Immunoassays Aged Amyloid beta-Peptides business.industry lcsh:R Biology and Life Sciences Proteins Macular degeneration medicine.disease eye diseases Complement system Health Care Ophthalmology 030104 developmental biology Geriatrics Macular Disorders Immune System Case-Control Studies Immunologic Techniques Enzymology biology.protein Cofactors (Biochemistry) iC3b lcsh:Q Dementia business Biomarkers |
| Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 5, p e0195751 (2018) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0195751 |
| Popis: | Activation of the alternative complement cascade has been implicated in the pathogenesis of age related macular degeneration (AMD) and Alzheimer's disease (AD). Amyloid β (Aβ), a component of drusen, may promote complement activation by inhibiting CFI bioactivity. We determined whether Aβ reduced CFI bioactivity and whether antibodies against Aβ including a monoclonal antibody, GSK933776 could restore CFI bioactivity. We also measured CFI bioactivity in plasma of subjects with AMD and AD. In support of the GSK933776 development program in AMD (geographic atrophy), we developed a quantitative assay to measure CFI bioactivity based on its ability to cleave C3b to iC3b, and repeated it in presence or absence of Aβ and anti-Aβ antibodies. Using this assay, we measured CFI bioactivity in plasma of 194 subjects with AMD, and in samples from subjects with AD that had been treated with GSK933776 as part of the GSK933776 development program in AD. Aβ reduced the CFI bioactivity by 5-fold and pre-incubation with GSK933776 restored CFI bioactivity. In subjects with AMD, plasma CFI levels and bioactivity were not significantly different from non-AMD controls. However, we detected a positive linear trend, suggesting increasing activity with disease severity. In subjects with AD, we observed a 10% and 27% increase in overall CFI bioactivity after treatment with GSK933776 during the second and third dose. Our studies indicate that CFI enzymatic activity can be inhibited by Aβ and be altered in proinflammatory diseases such as AMD and AD, in which deposition of Aβ and activation of the alternative complement cascade are believed to play a key role in the disease process. |
| Databáze: | OpenAIRE |
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