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

Abstract

Geographic atrophy (GA) is an advanced form of dry age-related macular degeneration (AMD), in which local inflammation and hyperactivity of the complement pathway have been implicated in its pathophysiology. This study explores whether any surrogate biomarkers are specifically associated with GA. Plasma from subjects with GA, intermediate dry AMD and non-AMD control were evaluated in 2 cohorts. Cohort 1 was assayed in a 320-analyte Luminex library. Statistical analysis was performed using non-parametric and parametric methods (Kruskal-Wallis, principal component analysis, partial least squares and multivariate analysis of variance (MANOVA) and univariate ANCOVAs). Bioinformatic analysis was conducted and identified connections to the amyloid pathway. Statistically significant biomarkers identified in Cohort 1 were then re-evaluated in Cohort 2 using individual ELISA and multiplexing. Of 320 analytes in Cohort 1, 273 were rendered measurable, of which 56 were identified as changing. Among these markers, 40 were identified in univariate ANCO-VAs. Serum amyloid precursor protein (sAPP) was analyzed by a separate ELISA and included in further analyses. The 40 biomarkers, sAPP and amyloid-β (Aβ) (1-42) (included for comparison) were evaluated in Cohort 2. This resulted in 11 statistically significant biomarkers, including sAPP and Aβ(1-40), but not Aβ(1-42). Other biomarkers identified included serum proteases-tissue plasminogen activator, tumor-associated trypsinogen inhibitor, matrix metalloproteinases 7 and 9, and non-proteases-insulin-like growth factor binding protein 6, AXL receptor tyrosine kinase, omentin, pentraxin-3 and osteopontin. Findings suggest that there is a preferential processing of APP to Aβ(1-40) over Aβ(1-42), and

Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications

“…While there is no cure for AMD, several vasodilation endothelial growth factor (VEGF) inhibitor therapies have been shown to be safe and effective for long-term prevention of vision loss in eAMD through the indefinite and recurrent treatment of CNV growth and exudation [ 84 , 85 , 86 ]. However, for neAMD, no such therapy is currently available for mitigating vision loss due to the loss of the RPE, PRC, and inner retinal layers in the regions of GA growth [ 87 ]. Since Aβ accumulation has been associated with all stages of AMD progression including drusen, CNV, and GA, recent attempts at identifying new therapeutic targets and interventions have looked toward further characterizing retinal Aβ in AMD [ 87 , 88 , 89 , 90 , 91 , 92 ].…”

“…However, for neAMD, no such therapy is currently available for mitigating vision loss due to the loss of the RPE, PRC, and inner retinal layers in the regions of GA growth [ 87 ]. Since Aβ accumulation has been associated with all stages of AMD progression including drusen, CNV, and GA, recent attempts at identifying new therapeutic targets and interventions have looked toward further characterizing retinal Aβ in AMD [ 87 , 88 , 89 , 90 , 91 , 92 ].…”

“…For neAMD, while the exact mechanism behind GA is unknown, growth of GA has been associated with deposition of inflammatory cellular debris in the Bruch’s membrane leading to the hyperactivation of the alternative complement pathway and resulting in RPE cell death [ 87 , 115 , 116 ]. Thus, Aβ deposition may be the main culprit behind GA pathology.…”

Sodium Iodate-Induced Degeneration Results in Local Complement Changes and Inflammatory Processes in Murine Retina

“…To investigate the immunological consequences of damaged RPE in a mouse model of retinal degeneration, systemic NaIO 3 administration was used to disrupt the integrity of the RPE cell layer (Figure 1). Due to a high variability in previous studies using NaIO 3 and the varying oxidising potency of this agent, a confirmation of retinal degeneration for each NaIO 3 study cycle was needed. In the present study, the intravenous application of NaIO 3 resulted in the formation of RPE cell agglomerations (blebs) at day 3 and RPE disruption at day 10 (Figure 1A).…”

“…Dysfunctional retinal pigment epithelium (RPE) and degenerated neurosensory retina play a central role in the pathobiology of age-related macular degeneration (AMD), the leading cause of blindness among the elderly in Western societies [1]. The oxidative events and inflammation drive the pathological changes in the retina and RPE during degeneration [2,3]. This is seen in animal studies, which were performed to elucidate the molecular interplay of oxidative stress and tissue-specific complement activation in the eyes [4].…”