Active Immunization with Amyloid-β 1–42 Impairs Memory Performance through TLR2/4-Dependent Activation of the Innate Immune System

Vollmar, Patrick; Kullmann, Jennifer; Thilo, Barbara; Claussen, Malte Christian; Rothhammer, Veit; Jacobi, H; Sellner, Johann; Nessler, Stefan; Korn, Thomas; Hemmer, Bernhard

doi:10.4049/jimmunol.1001765

Cited by 60 publications

(35 citation statements)

References 51 publications

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“…TLR2/3 deficiency attenuated the Aβ-induced changes in microglia. 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: Introductionsupporting

confidence: 70%

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: Introductionsupporting

confidence: 70%

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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“…Furthermore, these neuroprotective actions of naloxone were not limited to LPS, as (ϩ)-naloxone, (Ϫ)-naloxone, and naloxone methiodide all protected against ␤-amyloid-induced neurotoxicity and superoxide formation by microglia (Liu et al, 2002b). It is noteworthy that there is significant evidence that ␤-amyloid can activate microglia via TLR4-dependent pathways (Tang et al, 2008;Reed-Geaghan et al, 2009;Vollmar et al, 2010), suggesting, given the previously discussed evidence, that naloxone has nonstereoselective cross-ligand sensitivity of action at TLR4.…”

Section: The Clinical Predicament Of Ineffective Opioid Analgesia Andmentioning

confidence: 93%

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

Hutchinson

Shavit

Grace³

et al. 2011

Pharmacol Rev

347

315

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“…Among them, TLR4 is widely expressed in the brain and can detect endogenous agonists, such as the degradation products of macromolecules, heat shock proteins 60 and 70, and intracellular components of ruptured cells ( Johnson et al, 2003). TLR4 has been shown to participate in the cerebral inflammatory response related to ischemia reperfusion injury (Arslan et al, 2010;Brea et al, 2010), TBI ), Alzheimer's disease (Ding et al, 2011;Vollmar et al, 2010), and Parkinson's disease (Panaro et al, 2008;Waak et al, 2009). The TLR4 signaling pathway is mediated by interaction with the adapter protein myeloid differentiation factor 88 (MyD88), which leads to activation of nuclear factor-kappa B (NF-jB), and subsequent production of proinflammatory cytokines (Pulskens et al, 2008;Stetler et al, 2010).…”

Section: Introductionmentioning

confidence: 98%

Exogenous Administration of PACAP Alleviates Traumatic Brain Injury in Rats through a Mechanism Involving the TLR4/MyD88/NF-κB Pathway

Mao

Hua

Zhao

et al. 2012

Journal of Neurotrauma

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Pituitary adenylate cyclase-activating polypeptide (PACAP) is effective in reducing axonal damage associated with traumatic brain injury (TBI), and has immunomodulatory properties. Toll-like receptor 4 (TLR4) is an important mediator of the innate immune response. It significantly contributes to neuroinflammation induced by brain injury. However, it remains unknown whether exogenous PACAP can modulate TBI through the TLR4/adapter protein myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. In this study, we investigated the potential neuroprotective mechanisms of PACAP pretreatment in a weight-drop model of TBI. PACAP38 was microinjected intracerebroventricularly before TBI. Brain samples were extracted from the pericontusional area in the cortex and hippocampus. We found that TBI induced significant upregulation of TLR4, with peak expression occurring 24 h post-trauma, and that pretreatment with PACAP significantly improved motor and cognitive dysfunction, attenuated neuronal apoptosis, and decreased brain edema. Pretreatment with PACAP inhibited upregulation of TLR4 and its downstream signaling molecules MyD88, p-IκB, and NF-κB, and suppressed increases in the levels of the downstream inflammatory agents interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), in the brain tissue around the injured cortex and in the hippocampus. Administration of PACAP both in vitro and in vivo attenuated the ability of the TLR4 agonist lipopolysaccharide (LPS) to increase TLR4 protein levels. Therefore, PACAP exerts a neuroprotective effect in this rat model of TBI, by inhibiting a secondary inflammatory response mediated by the TLR4/MyD88/NF-κB signaling pathway in microglia and neurons, thereby reducing neuronal death and improving the outcome following TBI.

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Active Immunization with Amyloid-β 1–42 Impairs Memory Performance through TLR2/4-Dependent Activation of the Innate Immune System

Cited by 60 publications

References 51 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

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

Exogenous Administration of PACAP Alleviates Traumatic Brain Injury in Rats through a Mechanism Involving the TLR4/MyD88/NF-κB Pathway

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