Combined administration of resolvin E1 and lipoxin A4 resolves inflammation in a murine model of Alzheimer's disease

Kantarcı, Alpdoğan; Aytan, Nurgül; Palaska, Iro; Stephens, Danielle; Crabtree, Leah; Benincasa, C; Jenkins, Bruce G.; Carreras, Isabel; Dedeoglu, Alpaslan

doi:10.1016/j.expneurol.2017.11.005

Cited by 92 publications

(75 citation statements)

References 48 publications

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“…In addition to the strong behavioral effects observed with this SPM, RvE1 treatment also reduced hippocampal microglial activation phenotypes observed in Ts65Dn mice toward resting‐state phenotypes frequently observed in NS mice. Our observations corroborate other studies from the authors and others showing that SPMs reduce microglial activation in vivo (Kantarci et al, ; Lee et al, ) and in vitro models (Rey et al, ; Zhu et al, ). Also, within the hippocampus, we observed elevated levels of 15‐LOX‐2 in Ts65Dn mice and RvE1 treatment significantly reduced the levels of 15‐LOX‐2 in Ts65Dn without altering levels in NS mice.…”

Section: Discussionsupporting

confidence: 93%

RvE1 treatment prevents memory loss and neuroinflammation in the Ts65Dn mouse model of Down syndrome

Hamlett

Hjorth

Ledreux

et al. 2020

Glia

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Inflammation can be resolved by pro-homeostatic lipids called specialized proresolving mediators (SPMs) upon activation of their receptors. Dysfunctional inflammatory resolution is now considered as a driver of chronic neuroinflammation and Alzheimer's disease (AD) pathogenesis. We have previously shown that SPM levels were reduced and also that SPM-binding receptors were increased in patients with AD compared to age-matched controls. Individuals with Down syndrome (DS) exhibit accelerated acquisition of AD neuropathology, dementia, and neuroinflammation at an earlier age than the general population. Beneficial effects of inducing resolution in DS have not been investigated previously. The effects of the SPM resolvin E1 (RvE1) in a DS mouse model (Ts65Dn) were investigated with regard to inflammation, neurodegeneration, and memory deficits. A moderate dose of RvE1 for 4 weeks in middle-aged Ts65Dn mice elicited a significant reduction in memory loss, along with reduced levels of serum pro-inflammatory cytokines, and reduced microglial activation in the hippocampus of Ts65Dn mice but had no effects in age-matched normosomic mice. There were no observable adverse side effects in Ts65Dn or in normosomic mice. These findings suggest that SPMs may represent a novel drug target for individuals with DS and others at risk of developing AD.

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Section: Discussionsupporting

confidence: 93%

RvE1 treatment prevents memory loss and neuroinflammation in the Ts65Dn mouse model of Down syndrome

Hamlett

Hjorth

Ledreux

et al. 2020

Glia

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“…Notably, Fpr2/3 agonist treatment was able to reverse the effects of oAβ on microglial metabolism, targeting both the pentose phosphate pathway and the mitochondria. This data adds to the increasing evidence suggesting that Fpr2/3 not only suppresses pro-inflammatory mediator production [16,46], but aids in the regulation of the underlying metabolic changes that occur in activated immune cells, as we have recently shown in peripheral macrophages [14]. Importantly, microglia rapidly upregulate Fpr2/3 expression following inflammatory insult [47], and whilst the effects of its stimulation on neuroinflammation can be agonist dependent [48], selective Fpr2/3 activation contributes to neuroinflammatory resolution in a murine model of AD [46].…”

Section: Discussionsupporting

confidence: 69%

Reversal of β-amyloid induced microglial toxicityin vitroby activation of Fpr2/3

Wickstead

Karim

Manuel

et al. 2020

Preprint

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19Background and Purpose 20 Microglial inflammatory activity is thought to be a major contributor to the pathology of 21 neurodegenerative conditions such as Alzheimer's disease (AD), and strategies to restrain 22 their behaviour are under active investigation. Classically, anti-inflammatory approaches aim 23 to suppress pro-inflammatory mediator production, but exploitation of inflammatory resolution, 24 the endogenous process whereby an inflammatory reaction is terminated, has not been fully 25 investigated as a therapeutic approach in AD. In this study, we sought to provide proof-of-26 principal that the major pro-resolving actor, formyl peptide receptor 2, Fpr2, could be targeted 27 to reverse microglial activation induced by the AD-associated pro-inflammatory stimulus, 28 oligomeric β-amyloid (oAβ). 30Experimental Approach 31The immortalised murine microglial cell line BV2 was employed as a model system to 32 investigate the pro-resolving effects of the Fpr2 ligand QC1 upon oAβ-induced inflammatory, 33 oxidative and metabolic behaviour. Cytotoxic behaviour of BV2 cells was assessed through 34 use of co-cultures with retinoic acid-differentiated human SH-SY5Y cells. 36 Key Results 37Stimulation of BV2 cells with oAβ at 100nM did not induce classical inflammatory marker 38 production but did stimulate production of reactive oxygen species (ROS), an effect that could 39 be reversed by subsequent treatment with the Fpr2 ligand QC1. Further investigation revealed 40 that oAβ-induced ROS production was associated with NADPH oxidase activation and a shift 41 in BV2 cell metabolic phenotype, activating the pentose phosphate pathway and NADPH 42 production, changes that were again reversed by QC1 treatment. Microglial oAβ-stimulated 43 ROS production was sufficient to induce apoptosis of bystander SH-SY5Y cells, an effect that 44 could be prevented by QC1 treatment. 46 Conclusion and Implications 47In this study, we provide proof-of-concept data that indicate exploitation of the pro-resolving 48 receptor Fpr2 can reverse damaging oAβ-induced microglial activation. Future strategies 49 aiming to restrain neuroinflammation in conditions such as AD should examine pro-resolving 50 actors as a mechanism to harness the brain's endogenous healing pathways and limit 51 neuroinflammatory damage. 52 53 Keywords: Fpr2/3, Microglia, Oxidative stress, Alzheimer's disease 54 Background 55 56 AD is the single greatest cause of dementia, affecting approximately 4% of individuals aged 57 over 65 years and with a global disease burden of around 37 million individuals [1]. This figure 58 is set to increase as the population ages, and is expected to reach around 78 million people 59 by 2050 [2]. There are currently no effective treatments for the condition.60 61 Whilst the two core pathological lesions of AD, extracellular β-amyloid (Aβ) plaques and 62 intraneuronal tau tangles, have long been studied, the contribution to pathology provided by 63 neuroinflammation, and the role of the microglia in AD pathogenesis, has only recently been...

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“…Selectively targeting anti-inflammatory or inhibiting proinflammatory eicosanoid members may hold promise as a potential therapeutic strategy for managing cognitive and physical function (69,70). For instance, in a well-characterized rodent model of aging, the Fisher344 x Brown Norway rat, the administration of a genetically modified probiotic with Lactobacillus paracasei secreting angiotensin (1-7) led to an acute and long-term overexpression of circulating levels of angiotensin (1)(2)(3)(4)(5)(6)(7)71).…”

Section: Eicosanoidsmentioning

confidence: 99%

Crosstalk Between the Gut Microbiome and Bioactive Lipids: Therapeutic Targets in Cognitive Frailty

et al. 2020

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Cognitive frailty is a geriatric condition defined by the coexistence of cognitive impairment and physical frailty. This "composite" aging phenotype is associated with a higher risk of several adverse health-related outcomes, including dementia. In the last decade, cognitive frailty has gained increased attention from the scientific community that has focused on understanding the clinical impact and the physiological and pathological mechanisms of development and on identifying preventive and/or rehabilitative therapeutic interventions. The emergence of gut microbiome in neural signaling increased the interest in targeting the gut-brain axis as a modulation strategy. Multiple studies on gastroenteric, metabolic, and neurodegenerative diseases support the existence of a wide bidirectional communication network of signaling mediators, e.g., bioactive lipids, that can modulate inflammation, gut permeability, microbiota composition, and the gut-brain axis. This crosstalk between the gut-brain axis, microbiome, and bioactive lipids may emerge as the basis of a promising therapeutic strategy to counteract cognitive frailty. In this review, we summarize the evidence in the literature regarding the link between the gut microbiome, brain, and several families of bioactive lipids. In addition, we also explore the applicability of several bioactive lipid members as a potential routes for therapeutic interventions to combat cognitive frailty.

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Combined administration of resolvin E1 and lipoxin A4 resolves inflammation in a murine model of Alzheimer's disease

Cited by 92 publications

References 48 publications

RvE1 treatment prevents memory loss and neuroinflammation in the Ts65Dn mouse model of Down syndrome

RvE1 treatment prevents memory loss and neuroinflammation in the Ts65Dn mouse model of Down syndrome

Reversal of β-amyloid induced microglial toxicityin vitroby activation of Fpr2/3

Crosstalk Between the Gut Microbiome and Bioactive Lipids: Therapeutic Targets in Cognitive Frailty

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