Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer’s disease

McDonald, Claire; Hennessy, Edel; Rubio-Araiz, Ana; Keogh, Brian; McCormack, William; McGuirk, Peter; Reilly, Mary; Lynch, Marina A.

doi:10.1016/j.bbi.2016.07.143

Cited by 81 publications

(62 citation statements)

References 33 publications

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“…The finding that anti-TLR2 antibody increased LPS + Aβ-triggered phagocytosis of Aβ by microglia is consistent with our observation that treatment of APP/PS1 mice with the antibody twice monthly for 7 months from 7 to 14 months of age reduced Aβ accumulation [17]. It is also broadly in agreement with previous findings that indicated an increase in Aβ phagocytosis by primary microglia prepared from TLR2-deficient mice [15].…”

Section: Discussionsupporting

confidence: 93%

“…Without the two signals, activation will not occur and therefore inhibiting one of the signals should prevent inflammasome activation. Since Aβ interacts to induce at least some of its actions by engaging TLR2, as confirmed by the finding that anti-TLR2 antibody inhibits Aβ-induced changes [16, 17], we argued that anti-TLR2 antibody would therefore inhibit the inflammasome and downstream changes.…”

Section: Introductionsupporting

confidence: 55%

“…Consistently, our data have indicated that Aβ-induced increase in production of inflammatory cytokines was inhibited by pre-treating microglia with an anti-TLR2 antibody [16] and, interestingly, anti-TLR2 antibody prevented the Aβ-induced decrease in long-term potentiation (LTP), correlating with the evidence that the interaction of Aβ with TLR2 is associated with impaired cognition [14]. The evidence also indicates that administration of anti-TLR2 antibody to APP/PS1 mice improves cognitive function and this is associated with a decrease in microglial activation and with a decrease in Aβ accumulation, suggesting that it may affect phagocytosis [17]. …”

Section: Introductionmentioning

confidence: 72%

“…Anti-TLR2 antibody also attenuated the LPS + Aβ-induced increase in Iba1, which confirms that it exerts a modulatory effect on microglial activation. Treatment of APP/PS1 mice with anti-TLR2 antibody reduced CD68 immunoreactivity in the hippocampus providing further evidence of its modulatory effect on microglial activation [17]. …”

Section: Discussionmentioning

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: 93%

Section: Introductionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 72%

Section: Discussionmentioning

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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“…Interestingly, this was associated with an increase in M1 markers such as TNF-α and IFN-γ, a decrease in M2 markers including Fizz1 and YM1, and, paradoxically, an increase in the M2-associated marker IL-10 (114). These findings suggested that CD14 deletion shifts microglia activation to an immunomodulatory state, possibly by blocking TLR2 signaling, which contributes to inflammation and AD pathology (115). A drawback of TLR4 stimulation was the observed increase in taurelated pathology in 3xTgAD and rTg4510 mice (109).…”

Section: Microglia Activation In Admentioning

confidence: 98%

Microglia in Alzheimer’s disease

Sarlus

Heneka

2017

Journal of Clinical Investigation

642

561

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Plant‐derived peptides for the improvement of Alzheimer's disease: Production, functions, and mechanisms

Lin

Liu

et al. 2023

Food Frontiers

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Alzheimer's disease (AD) is a progressive neurodegenerative disease with an insidious onset that seriously affects human health. Plant-derived peptides have been found to hinder the development of AD pathologies, which is an excellent candidate for preventing AD. However, due to the excessively complicated pathogenesis of AD and the fact that most studies on the activity of plant-derived peptides are single and not deep enough, which restricted the development and application of plant-derived AD-prevention peptides (PADPs). This review summarized the currently available means of obtaining PADPs, in vitro and in vivo AD-prevention activity validation protocols, molecular pathways of PADPs, the structure-activity relationship between plant-derived peptides and AD-prevention activity, and some perspectives of current advanced technologies. This paper will help to develop the foundation for the production and exploitation of PADPs.

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Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer’s disease

Cited by 81 publications

References 33 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

Microglia in Alzheimer’s disease

Plant‐derived peptides for the improvement of Alzheimer's disease: Production, functions, and mechanisms

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