Background Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic neuroinflammation, known as part of pathology in Alzheimer’s disease (AD) brain. Methods Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in post mortem hippocampal tissue from AD-patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). Results Presence of SPMs and SPM receptors was demonstrated in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD - both in CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated to mini-mental state examination (MMSE) scores. Conclusions The resolution pathway exists in the brain and described alterations strongly suggest its dysfunction in AD. Correlations with MMSE suggest a connection with cognitive function in AD.

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.

Abstract. The use of supplements with omega-3 (ω3) fatty acids (FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is widespread due to proposed beneficial effects on the nervous and cardiovascular systems. Many effects of ω3 FAs are believed to be caused by down-regulation and resolution of inflammation. Alzheimer's disease (AD) is associated with inflammation mediated by microglia and astrocytes, and ω3 FAs have been proposed as potential treatments for AD. The focus of the present study is on the effects of DHA and EPA on microglial phagocytosis of the AD pathogen amyloid-␤ (A␤), on secreted and cellular markers of immune activity, and on production of brain-derived neurotrophic factor (BDNF). Human CHME3 microglial cells were exposed to DHA or EPA, with or without the presence of A␤ 42 . Phagocytosis of A␤ 42 was analyzed by flow cytometry in conjunction with immunocytochemistry using antibodies to cellular proteins. Secreted proteins were analyzed by ELISA. Both DHA and EPA were found to stimulate microglial phagocytosis of A␤ 42 . Phagocytosis of A␤ 42 was performed by microglia with a predominance of M2 markers. EPA increased the levels of BDNF in the culture medium. The levels of TNF-␣ were decreased by DHA. Both DHA and EPA decreased the pro-inflammatory M1 markers CD40 and CD86, and DHA had a stimulatory effect on the anti-inflammatory M2 marker CD206. DHA and EPA can be beneficial in AD by enhancing removal of A␤ 42 , increasing neurotrophin production, decreasing pro-inflammatory cytokine production, and by inducing a shift in phenotype away from pro-inflammatory M1 activation.

Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term “microbiota-gut-brain axis” from “gut-brain axis” underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer’s disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.

Experimental neural cell therapies, including donor neural stem/progenitor cells (NPCs) have been reported to offer beneficial effects on the recovery after an injury and to counteract inflammatory and degenerative processes in the central nervous system (CNS). The interplay between donor neural cells and the host CNS still to a large degree remains unclear, in particular in human allogeneic conditions. Here, we focused our studies on the interaction of human NPCs and microglia utilizing a co-culture model. In co-cultures, both NPCs and microglia showed increased survival and proliferation compared with mono-cultures. In the presence of microglia, a larger subpopulation of NPCs expressed the progenitor cell marker nestin, whereas a smaller group of NPCs expressed the neural markers polysialylated neural cell adhesion molecule, A2B5 and glial fibrillary acidic protein compared with NPC mono-cultures. Microglia thus hindered differentiation of NPCs. The presence of human NPCs increased microglial phagocytosis of latex beads. Furthermore, we observed that the expression of CD200 molecules on NPCs and the CD200 receptor protein on microglia was enhanced in co-cultures, whereas the release of transforming growth factor-β was increased suggesting anti-inflammatory features of the co-cultures. To conclude, the interplay between human allogeneic NPCs and microglia, significantly affected their respective proliferation and phenotype. Neural cell therapy including human donor NPCs may in addition to offering cell replacement, modulate host microglial phenotypes and functions to benefit neuroprotection and repair.

Resolution of inflammation terminates the inflammatory response in physiological conditions and promotes restoration and healing of the tissue; however, failure in resolution results in chronic inflammation that may lead to disease. Chronic inflammation mediated by microglia is a feature of Alzheimer's disease (AD) and can be a pathogenic factor in which both treatment targets and diagnostic markers may be found. In addition, there is evidence that the resolution pathway is altered in AD. It is therefore relevant to investigate whether amyloid-β (Aβ) peptide, the major component of senile plaque in AD brain, may have a negative influence on components of the resolution cascade. In this pursuit, we exposed microglia to Aβ42, and with bacterial lipopolysaccharides (LPS) for comparison with a general infectious stimulus. Differential effects were observed: LPS upregulated components of the resolution pathway including the LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2) and phosphorylated 5-lipoxygenase (p-5-LOX), as well as cholinergic alpha 7 nicotinic receptor (α7nAChR) and peroxisome proliferator-activated receptor (PPAR)-δ whereas Aβ42 had an opposite or insignificant effect. Our results indicate that LPS-induced changes in the microglia were conducive for resolution of inflammation, whereas these responses were absent or suppressed in microglia treated with Aβ42. Further studies may prove if Aβ42-induced dysfunction of resolution in microglia contributes to the impaired resolution in the AD brain, and if stimulation of microglial resolution constitutes a treatment strategy for AD.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and dementia. Accumulating evidence suggests that inflammation is involved in the pathogenesis of AD. Epidemiological studies suggest that use of anti-inflammatory drugs is associated with a lower incidence of AD. However, clinical trials with anti-inflammatory drugs have not been successful. Recent studies have shown that inflammation is resolved by a process that is mediated by a group of lipid mediators, so called specialized pro-resolving lipid mediators (SPMs). Unlike anti-inflammatory strategies, which usually involve inhibition of the synthesis of inflammatory mediators, stimulating the resolution of inflammation is aimed at ending inflammation in a similar fashion as under normal physiological conditions. We have previously shown that pathways of resolution are impaired in AD. Moreover, we found that SPMs can improve neuronal survival and increase microglial phagocytosis of amyloid beta (Aβ) in in vitro studies, indicating that stimulating resolution of inflammation may be a potential therapeutic target in AD. In this review, we summarize recent findings regarding resolution of inflammation in AD. We also discuss possible strategies to stimulate the resolution of inflammation in AD, specifically focusing on signaling pathways, including SPMs, their receptors and enzymes involved in their formation.

Cortical spreading depression (CSD), based on its similarities with peri-infarct depolarization, is an ideal model for investigating transformation from the ischemic penumbra to infarct core. However, the underlying mechanisms remain unclear. To our knowledge, this is the first study to use a middle cerebral artery occlusion ischemic-reperfusion (I/R) injury model to determine whether AMP-activated protein kinase (AMPK)-dependent autophagy contributes to the neuroprotection of CSD preconditioning in rat cortex. In this study, we topically applied a pledget soaked in 1 mol/L KCl solution on rat cortex for 2 h to elicite CSD or 1 mol/L NaCl solution as a control. The results demonstrated that CSD preconditioning significantly decreased the infarct volume, neurological deficits and neuronal apoptosis in the cortical penumbra of middle cerebral artery occlusion rats, which was inhibited by the autophagy inhibitor 3-methyladenine (3-MA, 200 nmol). Furthermore, CSD increased the protein levels of the autophagy markers LC3-II, Beclin-1 and the p-AMPK (Thr )/AMPK ratio at 12 h and decreased P62 and p-P70S6K (Thr ). Moreover, the AMPK inhibitor Compound C (20 mg/kg) down-regulated the LC3-II, p-AMPK (Thr )/AMPK and ULK1 levels, up-regulated the P62 and p-P70S6K (Thr ) levels induced by CSD. The neuroprotection of CSD is likely a result of AMPK-mediated autophagy activity and autophagy-induced neuronal cells apoptosis inhibition. These novel findings support a central role for AMPK and autophagy in CSD-induced ischemic tolerance. AMPK-mediated autophagy may represent a new target for stroke.