Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis

Abstract

Inflammation in the brain is a prominent feature in Alzheimer’s disease (AD). Recent studies suggest that chronic inflammation can be a consequence of failure to resolve the inflammation. Resolution of inflammation is mediated by a family of lipid mediators (LMs), and the levels of these specialized pro-resolving mediators (SPMs) are reduced in the hippocampus of those with AD. In the present study we combined analysis of LMs in the entorhinal cortex (ENT) from AD patients with in vitro analysis of their direct effects on neurons and microglia. We probed ENT, an area affected early in AD pathogenesis, by liquid chromatography-tandem mass spectrometry (LC-MS-MS), and found that the levels of the SPMs maresin 1 (MaR1), protectin D1 (PD1) and resolvin (Rv) D5, were lower in ENT of AD patients as compared to age-matched controls, while levels of the pro-inflammatory prostaglandin D2 (PGD2) were higher in AD. In vitro studies showed that lipoxin A4 (LXA4), MaR1, RvD1 and protectin DX (PDX) exerted neuroprotective activity, and that MaR1 and RvD1 down-regulated Aβ42-induced inflammation in human microglia. MaR1 exerted a stimulatory effect on microglial uptake of Aβ42. Our findings give further evidence for a disturbance of the resolution pathway in AD, and indicate that stimulating this pathway is a promising treatment strategy for AD.

Food for thought: how nutrition impacts cognition and emotion

“…70,71 DHA and SPMs are impaired at the periphery and in the brains of AD patients. 72,73 Interestingly, decreased DHA distribution in AD patient brains correlates with synaptic loss rather than amyloid beta (Aβ) deposition. 74 In addition, DHA or SPMs promote phagocytosis of Aβ42 by microglia 75 and modulate microglia number and activation in vivo.…”

“…Thus, blueberry juice significantly improved word list recall and paired associate learning in older men and women with agerelated memory decline that consumed it, relative to baseline, with paired associate learning also significantly improved relative to placebo controls. 97 A recent study 98 that measured similar cognitive tasks as those in the rodent studies, showed that freezedried blueberries (24 g/day, equivalent to one cup of fresh blueberries) for 90 days improved two measures of executive function in older adults (ages [60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75]. Participants in the blueberry group showed significantly fewer repetition errors in the California Verbal Learning test as well as reduced switch cost on a taskswitching test across study visits, relative to controls who consumed placebo powder.…”

Identification and Profiling of Specialized Pro-Resolving Mediators in Human Tears by Lipid Mediator Metabolomics

“…For example, these tissues, to name a few, include human blood [3, 4], lymph nodes [4], human brain [5], human placenta [6], breast milk [7, 8] and human kidney [2]. The SPM are clearly endogenous mediators that, given their presence in human organs and tissues, may have additional physiologic roles in their tissue of origin in addition to their functions in activating endogenous resolution circuits in inflammation.…”

Mechanisms Involved in the Remyelinating Effect of Sildenafil

“…Increased arginase activity has been associated with alternatively activated microglia/macrophages (M2) (Gensel and Zhang 2015, Ransohoff and improve neuronal survival and Aβ 2 phagocitosys in vitro (Zhu et al 2016). …”