Age-related increases in amyloid beta and membrane attack complex: evidence of inflammasome activation in the rodent eye

作者：Zhao Tom; Gao Jiangyuan; Van Jenifer; To Eleanor; Wang Aikun; Cao Sijia; Cui Jing Z; Guo Jian Ping; Lee Moonhee; McGeer Patrick L; Matsubara Joanne A^*

来源：Journal of Neuroinflammation, 2015, 12(1): 121.

DOI：10.1186/s12974-015-0337-1

• Age-related macular degeneration
• Membrane attack complex
• Amyloid beta
• NLRP3 inflammasome
• NF-kappa B
• RPE/choroid

Background: The membrane attack complex (MAC) is a key player in the pathogenesis of age-related macular degeneration (AMD) and is a putative activator of the NLRP3 inflammasome. Amyloid beta (A beta), a component of drusen deposits, has also been implicated in inflammasome activation by our work and those of others. However, the interactions of MAC and A beta are still poorly understood, especially their roles in aging and retinal degenerative pathologies. Since inflammasome activation may represent a key cellular pathway underlying age-related chronic inflammation in the eye, the purpose of this study is to identify the effects associated with MAC and inflammasome activation in the retinal pigment epithelium (RPE)/choroid and to evaluate the therapeutic merits of MAC suppression.
Methods: Adult Long-Evans rats were divided into treatment and control groups. Treatment groups received oral aurin tricarboxylic acid complex (ATAC), a MAC inhibitor, in drinking-water, and control groups received drinking-water alone (No ATAC). Groups were sacrificed at 7.5 or 11.5 months, after approximately 40 days of ATAC treatment. To study age-related changes of A beta and MAC in RPE/choroid, naive animals were sacrificed at 2.5, 7.5, and 11.5 months. Eye tissues underwent immunohistochemistry and western blot analysis for MAC, A beta, NF-kappa B activation, as well as cleaved caspase-1 and IL-18. Vitreal samples were collected and assessed by multiplex assays for secreted levels of IL-18 and IL-1 beta. Statistical analyses were performed, and significance level was set at p <= 0.05.
Results: In vivo studies demonstrated an age-dependent increase in MAC, A beta, and NF-kappa B activation in the RPE/choroid. Systemic ATAC resulted in a prominent reduction in MAC formation and a concomitant reduction in inflammasome activation measured by cleaved caspase-1 and secreted levels of IL-18 and IL-1 beta, but not in NF-kappa B activation. In vitro studies demonstrated A beta-induced MAC formation on RPE cells.
Conclusions: Age-dependent increases in A beta and MAC are present in the rodent outer retina. Our results suggest that suppressing MAC formation and subsequent inflammasome activation in the RPE/choroid may reduce chronic low-grade inflammation associated with IL-18 and IL-1 beta in the outer retina.

• 出版日期2015-6-24