Abstract
Alzheimer’s disease (AD) is one of the most common neurodegenerative disease. Accumulating evidences suggest an active role of inflammation in the pathogenesis of AD. Inflammation resolution is an active process that terminates inflammation and facilitates the restoration of inflamed tissue to homeostasis. Resolution of inflammation has been shown to be conducted by a group of specialized pro-resolving lipid mediators (SPMs) including lipoxins, resolvins, protectins, and maresins (MaRs). Recent studies have demonstrated that failure of inflammation resolution can lead to chronic inflammation and, hence, contribute to AD progression. We have previously shown that MaR1 can improve neuronal survival and increase microglial phagocytosis of Aβ. However, the effects of MaR1 on animal models of AD have not been reported. In this study, we aim to investigate the effects of MaR1 on behavioral deficits and pathological changes in a mouse model of AD. Mice received bilateral injections of Aβ42 protein into the hippocampus, followed by administration of MaR1 by intra-cerebroventricular injection. The behavioral changes in the mice were analyzed using Morris water maze. Immunohistochemistry, Fluoro-Jade B (FJB) staining, cytometric beads array (CBA), and western blot analysis were used to demonstrate molecular changes in the mice hippocampus and cortex. Our results showed that MaR1 treatment significantly improved the cognitive decline, attenuated microglia and astrocyte activation. In addition, we found that MaR1 decreased the pro-inflammatory cytokines TNF-α, IL-6, and MCP-1 production induced by Aβ42 and increased the anti-inflammatory cytokines IL-2, IL-10 secretion with or without Aβ42 stimulation. Moreover, western blot results showed that MaR1 up-regulated the levels of proteins related to survival pathway including PI3K/AKT, ERK and down-regulated the levels of proteins associated with inflammation, autophagy, and apoptosis pathways such as p38, mTOR and caspase 3. To conclude, MaR1 improved the cognitive decline, ameliorated pro-inflammatory glia cells activation via improving survival, enhancing autophagy, inhibiting inflammation and apoptosis pathways. In conclusion, this study shows that inflammation resolution may be a potential therapeutic target for AD.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia, with no existing treatment that can significantly delay or reverse AD-associated cognitive decline or pathological changes
Inflammation resolution is mediated by a group of lipid mediators called specialized pro-resolving lipid mediators (SPMs) including lipoxins (LXs), resolvins (Rvs), protectins (NPDs), and maresins (MaRs), all of which are biosynthesized from polyunsaturated fatty acids (PUFAs) via cyclooxygenases (COXs) and lipoxygenases (LOXs) (Serhan, 2014)
We have previously showed that inflammation resolution is impaired in the AD brains and stimulating resolution of inflammation by SPMs has proved to be beneficial in cellular models of AD, indicating that resolution of inflammation by SPMs may be a potential therapeutic target for AD (Wang et al, 2015; Zhu et al, 2016)
Summary
Alzheimer’s disease (AD) is the most common cause of dementia, with no existing treatment that can significantly delay or reverse AD-associated cognitive decline or pathological changes. There is a plethora of evidence that support the Aβ hypothesis: patients with an extra copy of chromosome 21, where the APP gene locates, develop dementia at an early age; APP transgenic mice exhibit significant cognitive impairment; the toxicity of Aβ has been documented extensively in in vitro studies (Del Bo et al, 1995; Combs et al, 2001; Wicklund et al, 2010). Microglia activation as well as elevated proinflammatory mediators observed in postmortem AD brains and in AD mice models support that chronic inflammation is an integral part of AD pathogenesis (Heppner et al, 2015). Studies have found that reduced SPMs lead to failure of inflammation resolution that can contribute to chronic inflammation diseases such as atherosclerosis (Fredman et al, 2016), dry eye pathogenesis (Gao et al, 2015) as well as AD (Wang et al, 2015)
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