Localisation of Formyl-Peptide Receptor 2 in the Rat Central Nervous System and Its Role in Axonal and Dendritic Outgrowth

Ho, Christabel Fung‐Yih; Ismail, Nadia Binte; Koh, Joled Kong-Ze; Gunaseelan, Saravanan; Low, Yi-Hua; Ng, Yee‐Kong; Chua, John Jia En; Ong, Wei‐Yi

doi:10.1007/s11064-018-2573-0

Cited by 43 publications

(51 citation statements)

References 60 publications

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“…Auto-oxidation forms isoprostanes that are indicators of oxidative stress and are neurotoxic. On the other hand, resolvins and neuroprotectins resolve inflammation and are involved in the repair of post-mitotic brain cells (Heras-Sandoval et al, 2016;Ho et al, 2018). Therefore, a balance in the levels of n-6 to n-3 levels can impact neuronal function and survival.…”

Section: Pufa Inflammation and Oxidative Stressmentioning

confidence: 99%

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

et al. 2020

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Alzheimer's disease (AD) pathology is characterized by an early and prolonged decrease in the amyloid peptide (Aβ) levels concomitant with a later increase in phosphotau concentrations in cerebrospinal fluid (CSF). We propose that changes in lipid metabolism can contribute to the abnormal processing of Aβ 42 in AD. Our aim was to determine if polyunsaturated fatty acid (PUFA) metabolism can differentiate presymptomatic AD from normal aging and symptomatic AD. Using neuropsychology measures and Aβ 42 /T-tau in cerebrospinal fluid (CSF), we classify three groups of elderly study participants: cognitively healthy with normal Aβ 42 /T-tau (CH-NAT), cognitively healthy with pathological Aβ 42 /T-tau (CH-PAT), and AD individuals. We determined the size distribution and the concentration of CSF particles using light scattering and quantified PUFA composition in the nanoparticulate (NP) fraction, supernatant fluid (SF), and unesterified PUFA levels using gas chromatography combined with mass spectrometry. Four PUFAs (C20:2n-6, C20:3n-3, C22:4n-6, C22:5n-3) were enriched in NP of AD compared with CH-NAT. C20:3n-3 levels were higher in the NP fraction from AD compared with CH-PAT. When normalized to the number of NPs in CSF, PUFA levels were significantly higher in CH-NAT and CH-PAT compared with AD. In the SF fractions, only the levels of docosahexaenoic acid (DHA, C22:6n-3) differentiated all three clinical groups. Unesterified DHA was also higher in CH-NAT compared with the other clinical groups. Our studies also show that NP PUFAs in CH participants negatively correlate with CSF Aβ 42 while C20:4n-6, DHA, and n-3 PUFAs in the SF fraction positively correlate with T-tau. The profile of PUFAs in different CSF fractions that correlate with Aβ 42 or with T-tau are different for CH-NAT compared with CH-PAT. These studies show that PUFA metabolism is associated with amyloid and tau processing. Importantly, higher PUFA levels in the cognitively healthy study participants with abnormal Aβ 42 /T-tau suggest that PUFA enhances the cognitive resilience of the pre-symptomatic AD population. We propose that interventions that

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Section: Pufa Inflammation and Oxidative Stressmentioning

confidence: 99%

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

et al. 2020

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“…ChemR23 has been identified in the prefrontal cortex, hippocampus, and brainstem [149]. These receptors are also expressed in microglial cells [123,150], neurons [122,124], and astrocytes [126]. Specialized Pro-resolving Mediator (SPM) synthesis pathway and receptors.…”

Section: Epa-derived Spmsmentioning

confidence: 99%

“…The receptor of RvD1 is lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) in rodents and G protein coupling receptor 32 (GPR32) in humans [116]. Several brain structures express ALX/FPR2: brainstem, spinal cord, hypothalamus, cortex, hippocampus, cerebellum, and striatum [122]. At the cellular level, these receptors are expressed in microglial cells [123], neurons [122,124], and astrocytes [125,126].…”

Section: Introductionmentioning

confidence: 99%

“…Several brain structures express ALX/FPR2: brainstem, spinal cord, hypothalamus, cortex, hippocampus, cerebellum, and striatum [122]. At the cellular level, these receptors are expressed in microglial cells [123], neurons [122,124], and astrocytes [125,126]. Via these receptors, RvD1 regulates micro-RNAs (miRNAs), which play a key role in modulating the expression of target genes such as inflammatory genes [123,125,[127][128][129].…”

Section: Introductionmentioning

confidence: 99%

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n-3 Polyunsaturated Fatty Acids and Their Derivates Reduce Neuroinflammation during Aging

et al. 2020

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Aging is associated to cognitive decline, which can lead to loss of life quality, personal suffering, and ultimately neurodegenerative diseases. Neuroinflammation is one of the mechanisms explaining the loss of cognitive functions. Indeed, aging is associated to the activation of inflammatory signaling pathways, which can be targeted by specific nutrients with anti-inflammatory effects. Dietary n-3 polyunsaturated fatty acids (PUFAs) are particularly attractive as they are present in the brain, possess immunomodulatory properties, and are precursors of lipid derivates named specialized pro-resolving mediators (SPM). SPMs are crucially involved in the resolution of inflammation that is modified during aging, resulting in chronic inflammation. In this review, we first examine the effect of aging on neuroinflammation and then evaluate the potential beneficial effect of n-3 PUFA as precursors of bioactive derivates, particularly during aging, on the resolution of inflammation. Lastly, we highlight evidence supporting a role of n-3 PUFA during aging.

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“…Expression of FPR2 within the brain has been reported in the endothelium and in selected hippocampal and cerebellar neurones [19], but it is also expressed by microglia [20], and is rapidly upregulated following inflammatory insult [21]. Significantly, FPR2 expression has been reported in inflammatory cells infiltrating Aβ plaques in AD [22], is involved in chemotaxis to high concentrations of Aβ [23] and has been indirectly implicated in microglial Aβ phagocytosis [24].…”

Section: Introductionmentioning

confidence: 99%

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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Localisation of Formyl-Peptide Receptor 2 in the Rat Central Nervous System and Its Role in Axonal and Dendritic Outgrowth

Cited by 43 publications

References 60 publications

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

n-3 Polyunsaturated Fatty Acids and Their Derivates Reduce Neuroinflammation during Aging

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

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