Prestimulation of Microglia Through TLR4 Pathway Promotes Interferon Beta Expression in a Rat Model of Alzheimer’s Disease

Yousefi, Niloufar; Sotoodehnejadnematalahi, Fattah; Heshmati-Fakhr, Nooshin; Sayyah, Mohammad; Hoseini, Masoud; Ghassemi, Soheil; Aliakbari, Shayan; Pourbadie, Hamid Gholami

doi:10.1007/s12031-018-1249-1

Cited by 22 publications

(13 citation statements)

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“…However, the mechanism of neuroinflammation needs to be further investigated. TLR4 is a transmembrane protein that is predominantly expressed in microglia of the central nervous system [26,27]. Involvement of TLR4 initiates intracellular signaling pathways, leading to the synthesis and secretion of inflammatory cytokines and chemokines, typically by activating NF-κB and subsequent gene transcription and protein synthesis [4,28].…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4/nuclear factor-kappa B pathway is involved in radicular pain by encouraging spinal microglia activation and inflammatory response in a rat model of lumbar disc herniation

Zhu

Huang

Hu³

et al. 2021

Korean J Pain

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Background: Lumbar disc herniation (LDH) is a common cause of radicular pain, but the mechanism is not clear. In this study, we investigated the engagement of toll-like receptor 4 (TLR4) and the nuclear factor-kappa B (NF-κB) in radicular pain and its possible mechanisms. Methods: An LDH model was induced by autologous nucleus pulposus (NP) implantation, which was obtained from coccygeal vertebra, then relocated in the lumbar 4/5 spinal nerve roots of rats. Mechanical and thermal pain behaviors were assessed by using von Frey filaments and hotplate test respectively. The protein level of TLR4 and phosphorylated-p65 (p-p65) was evaluated by western blotting analysis and immunofluorescence staining. Spinal microglia activation was evaluated by immunofluorescence staining of specific relevant markers. The expression of proand anti-inflammatory cytokines in the spinal dorsal horn was measured by enzyme linked immunosorbent assay. Results: Spinal expression of TLR4 and p-NF-κB (p-p65) was significantly increased after NP implantation, lasting up to 14 days. TLR4 was mainly expressed in spinal microglia, but not astrocytes or neurons. TLR4 antagonist TAK242 decreased spinal expression of p-p65. TAK242 or NF-κB inhibitor pyrrolidinedithiocarbamic acid alleviated mechanical and thermal pain behaviors, inhibited spinal microglia activation, moderated spinal inflammatory response manifested by decreasing interleukin (IL)-1β, IL-6, tumor necrosis factor-α expression and increasing IL-10 expression in the spinal dorsal horn. Conclusions: The study revealed that TLR4/NF-κB pathway participated in radicular pain by encouraging spinal microglia activation and inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4/nuclear factor-kappa B pathway is involved in radicular pain by encouraging spinal microglia activation and inflammatory response in a rat model of lumbar disc herniation

Zhu

Huang

Hu³

et al. 2021

Korean J Pain

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“…The underlying mechanism may involve TRIF-dependent signaling. Pretreatment with LPS or MPL was also found to enhance the expression of the neuroprotective cytokine IFN-β both in vivo and in vitro (Yousefi et al, 2019). MPL, a detoxified derivative of LPS, activates TLR4 to trigger the inflammatory response.…”

Section: Alzheimer Disease and Toll-like Receptormentioning

confidence: 96%

TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment

Zhou

Chen

et al. 2020

Front. Neurosci.

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Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta and formation of intracellular neurofibrillary tangles. Microglia activation and neuroinflammation play important roles in the pathogenesis of AD; Toll-like receptor 4 (TLR4)—a key component of the innate immune system—in microglia is also thought to be involved based on the observed association between TLR gene polymorphisms and AD risk. TLR4 has been shown to exert both detrimental and beneficial effects on AD-related pathologies. In preclinical models, experimental manipulations targeting TLR4 were shown to improve learning and memory, which was related to inhibition of pro-inflammatory cytokine release and reduction of oxidative stress. In this review, we summarize the key evidence supporting TLR4 as a promising therapeutic target in AD treatment.

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“…In an experimental study of immunological preconditioning with TLR4 agonist LPS, Monophosphoryl lipid A (MPL) was shown to upregulate IFN-β-positive cells and reduce hippocampal TNF-α-positive cells of Aβ-treated rats. Reduction in TNF-α could be the result of increased IFN-β levels via the TLR4 signaling axis [119]. The release of IFN-β upon pre-treatment with TLR4 agonists might be a promising neuroprotective strategy against neurodegeneration in AD.…”

Section: Effects Of Tlr4 Blockade In Admentioning

confidence: 99%

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Paudel

Angelopoulou

Piperi

et al. 2020

Cells

181

128

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

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Prestimulation of Microglia Through TLR4 Pathway Promotes Interferon Beta Expression in a Rat Model of Alzheimer’s Disease

Cited by 22 publications

References 50 publications

Toll-like receptor 4/nuclear factor-kappa B pathway is involved in radicular pain by encouraging spinal microglia activation and inflammatory response in a rat model of lumbar disc herniation

Toll-like receptor 4/nuclear factor-kappa B pathway is involved in radicular pain by encouraging spinal microglia activation and inflammatory response in a rat model of lumbar disc herniation

TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

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