A monoclonal antibody targeting amyloid β (Aβ) restores complement factor I bioactivity: Potential implications in age-related macular degeneration and Alzheimer’s disease

Abstract

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.

Microglia Contribution to the Regulation of the Retinal and Choroidal Vasculature in Age-Related Macular Degeneration

“…Aged CXCR5 −/− mice present retinal degeneration, with photoreceptor cell death, upregulation of TNF and breakdown of the outer blood-retinal barrier. Moreover, these animals exhibit drusen-like deposits and the presence of Aβ and Cryab, two abundant proteins that are present in Bruch's membrane and choroidal tissues of AMD patients [167,168]. Aβ and Cryab induce activation of the alternative complement cascade and are a target for microglia adaptive immune responses [167,169].…”

Impacts of CR1 genetic variants on cerebrospinal fluid and neuroimaging biomarkers in alzheimer’s disease

“…As we all known, Aβ is one important pathological characteristic of AD [27], which may induce the activation of the classical complement pathway in AD brains [28,29]. Moreover, CR1 is a necessary component of complement system, and it has been reported to have a close connection with amyloid plaque burden during aging [30,31].…”

Plasma biomarkers of the amyloid pathway are associated with geographic atrophy secondary to age-related macular degeneration

“…Aβ may also induce toxicity at the PR level by impacting their ribosomal machinery and oxidative phosphorylation by increasing phosphorylation of tau protein and dysregulating glycogen synthase kinase-3 beta (GSK3β) [29]. We have recently shown that Aβ can inhibit the activity of CFI, one of the key breaks in the alternative complement pathway leading to a shift in overproduction of C3b (active pathway) in lieu of production of iC3b which as a consequence inactivates the pathway [30]. Increased C3b leads to the eventual production of C5b678(9) membrane attack complex via the alternative complement pathway.…”

“…Increased C3b leads to the eventual production of C5b678(9) membrane attack complex via the alternative complement pathway. However, a clinical study attempting to block the action of Aβ via systemic administration of an anti-Aβ antibody (GSK933776) failed to reduce GA progression rate [31], probably because of the inability of systemic administration to achieve sufficiently high concentrations of the antibody at the level of the RPE/Bruch's membrane interphase [30].…”

“…Aβ molecules are present as monomeric, oligomeric and fibrillar conformations with oligomeric driving pathologic processes [32]. The Aβ pathway may also indirectly influence heightened complement activation of the alternative complement pathway [26,30,33]. APP also undergoes extensive processing, and mutations in APP are associated with familial Alzheimer's disease (AD) [34].…”