Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1 mice

Holland, Ross; McIntosh, Allison; Finucane, Orla M.; Mela, Virginia; Rubio-Araiz, Ana; Timmons, George A.; McCarthy, Sarah A; Gun’ko, Yurii K.; Lynch, Marina A.

doi:10.1016/j.bbi.2017.10.017

Cited by 149 publications

(129 citation statements)

References 40 publications

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“…Here we show that LPS + Aβ increased glycolysis in microglia, consolidating our recent finding in microglia [8] and other findings in BV2 cells [9, 10], and showing that inflammatory stimuli exert this action in microglia as they do in macrophages [1]. A significant finding of the current study is that anti-TLR2 antibody attenuated the LPS + Aβ-induced effect on glycolysis and also on 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), a bifunctional enzyme with predominantly kinase activity that leads to an increase in phosphofructokinase activity and thereby drives glycolysis [37–39].…”

Section: Discussionsupporting

confidence: 91%

“…A persistent reliance on glycolysis in microglia, because it is metabolically inefficient, will inevitably lead to reduced function, including phagocytosis, and may ultimately contribute to changes such as amyloid accumulation in AD. In this context, it is interesting that microglia from APP/PS1 mice exhibit a glycolytic phenotype [8]. …”

Section: Discussionmentioning

confidence: 99%

“…It has also been shown in BV2 cells that stimulation with lipopolysaccharide (LPS) + IFNγ increased glucose consumption, hexokinase activity and lactate production which are indicative of glycolysis [9], while LPS alone increased glycolysis and decreased mitochondrial metabolism also in BV2 cells [10]. Importantly, we have demonstrated that microglia prepared from transgenic mice that overexpress human amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice) had both an inflammatory and glycolytic phenotype [8] while amyloid-β (Aβ) stimulates inflammatory cytokine production in LPS-primed microglia [11]. …”

Section: Introductionmentioning

confidence: 92%

“…Specifically, interferon-γ (IFNγ) triggered activation of primary cultured microglia, increased production of inflammatory cytokines and shifted the cells towards glycolysis [8]. It has also been shown in BV2 cells that stimulation with lipopolysaccharide (LPS) + IFNγ increased glucose consumption, hexokinase activity and lactate production which are indicative of glycolysis [9], while LPS alone increased glycolysis and decreased mitochondrial metabolism also in BV2 cells [10].…”

Section: Introductionmentioning

confidence: 99%

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Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Rubio-Araiz

Finucane

Keogh

et al. 2018

J Neuroinflammation

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BackgroundMicroglia are multifunctional cells that are primarily neuroprotective and a deficit in their functional integrity is likely to be a contributory factor in the deteriorating neuronal function that occurs with age and neurodegeneration. One aspect of microglial dysfunction is reduced phagocytosis, and this is believed to contribute to the accumulation of amyloid-β (Aβ) in Alzheimer’s disease (AD). Therefore, improving phagocytosis should be beneficial in limiting the amyloidosis that characterises AD.MethodsHere, we investigated whether an antibody that targets toll-like receptor (TLR)2 might attenuate the inflammatory and metabolic changes induced by lipopolysaccharide (LPS) and amyloid-β. The impact on phagocytosis was assessed by immunohistochemistry. We evaluated the metabolic changes with the SeaHorse Extracellular Flux Analyser and studied the expression of key enzymes driving glycolysis by western blotting. For all experiments, statistical significance was determined by unpaired Student’s t test and two-way analysis of variance (ANOVA).ResultsWe have reported that, when exposed to an inflammatory stimulus, microglia switch their metabolism towards the metabolically- inefficient glycolysis; this potentially impacts on metabolically demanding functions like phagocytosis. Anti-TLR2 antibody increased phagocytosis of Aβ in LPS + Aβ-stimulated microglia and this was linked with the ability of the antibody to attenuate the LPS + Aβ-triggered inflammasome activation. LPS + Aβ increased glycolysis in microglia and increased the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3, an enzyme that plays a key role in driving glycolysis; these effects were inhibited when cells were incubated with the anti-TLR2 antibody. The data also show that antibody treatment increased oxidative metabolism.ConclusionsThus, microglia with an inflammatory phenotype, specifically cells in which the inflammasome is activated, are glycolytic; this may compromise the metabolic efficiency of microglia and thereby provide an explanation for the reduced phagocytic function of the cells. We propose that, by restoring oxidative metabolism and reducing inflammasome activation in microglia, phagocytic function is also restored.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1281-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Rubio-Araiz

Finucane

Keogh

et al. 2018

J Neuroinflammation

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“…These findings establish a link between inflammation and iron handling. Our recent findings demonstrated that IFNγ‐induced changes in microglia included the production of inflammatory cytokines together with iron retention, perhaps driven by an upregulation in mRNA expression of ferritin and a downregulation of ferroportin and this provides further evidence that iron accumulation occurs in activated microglia.…”

Section: Introductionsupporting

confidence: 58%

Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice

et al. 2019

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Among the changes that typify Alzheimer's disease (AD) are neuroinflammation and microglial activation, amyloid deposition perhaps resulting from compromised microglial function and iron accumulation. Data from Genome Wide Association Studies (GWAS) identified a number of gene variants that endow a significant risk of developing AD and several of these encode proteins expressed in microglia and proteins that are implicated in the immune response. This suggests that neuroinflammation and the accompanying microglial activation are likely to contribute to the pathogenesis of the disease. The trigger(s) leading to these changes remain to be identified. In this study, we set out to examine the link between the inflammatory, metabolic and iron-retentive signature of microglia in vitro and in transgenic mice that overexpress the amyloid precursor protein (APP) and presenilin 1 (PS1; APP/ PS1 mice), a commonly used animal model of AD. Stimulation of cultured microglia with interferon (IFN)γ and amyloid-β (Aβ) induced an inflammatory phenotype and switched the metabolic profile and iron handling of microglia so that the cells became glycolytic and iron retentive, and the phagocytic and chemotactic function of the cells was reduced. Analysis of APP/PS1 mice by magnetic resonance imaging (MRI) revealed genotype-related hypointense areas in the hippocampus consistent with iron deposition, and immunohistochemical analysis indicated that the iron accumulated in microglia, particularly in microglia that decorated Aβ deposits. Isolated microglia prepared from APP/PS1 mice were characterized by a switch to a glycolytic and iron-retentive phenotype and phagocytosis of Aβ was reduced in these cells. This evidence suggests that the switch to glycolysis in microglia may kick-start a cascade of events that ultimately leads to microglial dysfunction and Aβ accumulation.Brain Pathology 29 (2019) 606-621

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The Role of Immunity in Alzheimer's Disease

McManus

2022

Advanced Biology

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Based on this, it has been suggested that reducing co-morbidities in the elderly and extending the period of healthy aging will have a significant impact on decreasing the number of individuals with such impairments in 2050, with a knock-on effect of reducing the cost of dementia care.It is widely acknowledged that neuroinflammation is a critical step on the road to dementia. It is produced as a reaction to the ongoing protein deposition and cell loss observed in individuals with cognitive impairment and it has been argued that such inflammatory factors can in turn exacerbate ongoing cellular changes and hasten the progression to severe cognitive decline. This review will detail the role of the innate and adaptive immune system in the progression of AD. Specifically we will cover microglia mediated-neuroinflammation and the contribution of peripheral cells, namely T cells, on the progression to cognitive decline and the potential therapies that are under development to tackle these pathways will be discussed. Alzheimer's DiseaseThe most common cause of cognitive impairment or dementia is AD. This accounts for 60-80% of dementia cases [5] and is characterized by the build-up of two different proteins, amyloid-β (Aβ) and tau, along with cognitive changes. Aβ is cleaved from amyloid precursor protein (APP) and these monomers aggregate into oligomers and fibrils, ultimately forming Aβ-containing plaques that are 200-650 μm 2 in size. [6] Aβ can also undergo posttranslational modifications such as phosphorylation and nitration, which accelerate this process. [7,8] Tau is a protein found in neurons that is involved in microtubule stabilization, however in AD (and other Frontotemporal dementias -FTDs) tau becomes hyperphosphorylated and accumulates forming neurofibrillary tangles (NFTs). These deposits vary considerably in size from 10 to 500 μm 2 . [9] The severity of pathological changes (particularly the NFTs) correlate with neuronal loss and the increasing cognitive decline in those with AD. [10][11][12] The observed cognitive impairment in AD differs significantly across disease stages, and ranges from mild cognitive impairment (MCI), which can progress to moderate and then severe dementia. Indeed 68-80% of those who receive an initial diagnosis of MCI go on to develop AD within 6 years. [13][14][15] MCI is the first stage of cognitive decline and features initial With the increase in the aging population, age-related conditions such as dementia and Alzheimer's disease will become ever more prevalent in society. As there is no cure for dementia and extremely limited therapeutic options, researchers are examining the mechanisms that contribute to the progression of cognitive decline in hopes of developing better therapies and even an effective, long-lasting treatment for this devastating condition. This review will provide an updated perspective on the role of immunity in triggering the changes that lead to the development of dementia. It will detail the latest findings on Aβ-and tau-induced microglial activation, i...

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Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1 mice

Cited by 149 publications

References 40 publications

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice

The Role of Immunity in Alzheimer's Disease

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