STIMULATE RESOLUTION OF INFLAMMATION AS A STRATEGY FOR ALZHEIMER'S DISEASE

Abstract

Background: It is well established that inflammation exists in the brain afflicted byAlzheimer’s disease in the formof activated glial cells and elevated levels of cytokines such as interleukin (IL)-1b. Inflammation can contribute to the pathology by directly causing neurodegeneration and by stimulating Ab production. However, inflammation also has a beneficial aspect. The beneficial activities of inflammation are concentrated in the end stage of inflammation: the resolution phase in which clearance of debris and apoptotic cells and the restoration of tissue occurs in order to promote return to homeostasis. Resolution is actively induced by specialized pro-resolving lipid mediators (SPMs). The chronic inflammation in AD suggests a failure of resolution, evidence for which has been found in post-mortem AD brain and cerebrospinal fluid. Our hypothesis is that promotion of resolution may be a potential therapeutic target in AD by stimulating restorative and protectivemechanisms. The aim of this studywas to investigate the potential of the SPMmaresin-1 (MaR1) to induce protective and restorative effects in invitromodels of neurodegeneration and exposure toAb 42.Methods:Cells of the human microglial cell line (CHME-3) were incubated with Ab 42 and the effects of MaR1 on Ab 42 phagocytosis and microglial phenotype were analysed by flow-cytometry. The human neuroblastoma cell line SH-SY5Y differentiated with retinoic acid (RA) and brain derived neurotropic factor (BDNF), was used to investigate the effects of MaR1 on neuronal toxicity and viability following incubationwith staurosporine (STS). Secretory products such as interleukin-6 (IL-6), tumour necrosis factor (TNF)-a were analysed by ELISA. Enzymes involved in producing SPMs, such as 15-lipoxygenase (15-LOX) and receptors for SPMs, were investigated by western blot and immunocytochemistry. Results: MaR1 increased phagocytosis of Ab 42 and down-regulated the M1 markers CD80 and CD86 in microglia, and counteracted neuronal cell death induced by STS in differentiated neuroblastoma cells.Conclusions:Our observations indicate the protective role of MaR1 in attenuating inflammation in microglial cells and improving neuronal survival in a neuronal model, suggesting that stimulating resolution of inflammation can be an attractive strategy for AD. Further analysis will focus on mechanisms underlying neuroprotective effects of MaR1.