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Fibrillar Amyloid-β Peptides Activate Microglia via TLR2 Implications for Alzheimer's Disease

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
The Journal of Immunology (Impact Factor: 5.36). 12/2008; 181(10):7254-62. DOI: 10.4049/jimmunol.181.10.7254
Source: PubMed

ABSTRACT Microglial activation is an important pathological component in brains of patients with Alzheimer's disease (AD), and fibrillar amyloid-beta (Abeta) peptides play an important role in microglial activation in AD. However, mechanisms by which Abeta peptides induce the activation of microglia are poorly understood. The present study underlines the importance of TLR2 in mediating Abeta peptide-induced activation of microglia. Fibrillar Abeta1-42 peptides induced the expression of inducible NO synthase, proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), and integrin markers (CD11b, CD11c, and CD68) in mouse primary microglia and BV-2 microglial cells. However, either antisense knockdown of TLR2 or functional blocking Abs against TLR2 suppressed Abeta1-42-induced expression of proinflammatory molecules and integrin markers in microglia. Abeta1-42 peptides were also unable to induce the expression of proinflammatory molecules and increase the expression of CD11b in microglia isolated from TLR2(-/-) mice. Finally, the inability of Abeta1-42 peptides to induce the expression of inducible NO synthase and to stimulate the expression of CD11b in vivo in the cortex of TLR2(-/-) mice highlights the importance of TLR2 in Abeta-induced microglial activation. In addition, ligation of TLR2 alone was also sufficient to induce microglial activation. Consistent to the importance of MyD88 in mediating the function of various TLRs, antisense knockdown of MyD88 also inhibited Abeta1-42 peptide-induced expression of proinflammatory molecules. Taken together, these studies delineate a novel role of TLR2 signaling pathway in mediating fibrillar Abeta peptide-induced activation of microglia.

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    • "Chronic inflammation is associated with early development and acceleration of neurodegenerative diseases such as Alzheimer’s disease [39,40]. Therefore, we analyzed the expression of Rcor1 and Rcor2 in P8 cortices and hippocampi. "
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    ABSTRACT: Background Aging is characterized by a low-grade systemic inflammation that contributes to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD). However, little knowledge is currently available on the molecular processes leading to chronic neuroinflammation. In this context, recent studies have described the role of chromatin regulators in inflammation and longevity including the REST corepressor (Rcor)-2 factor, which seems to be involved in an inflammatory suppressive program. Methods To assess the impact of Rcor2 in age-related inflammation, gene expression levels were quantified in different tissues and ages of the spontaneous senescence-accelerated P8 mouse (P8) using the SAMR1 mouse (R1) as a control. Specific siRNA transfection in P8 and R1 astrocyte cultures was used to determine Rcor2 involvement in the modulation of neuroinflammation. The effect of lipopolysaccharide (LPS) treatment on Rcor2 levels and neuroinflammation was analyzed both in vivo and in vitro. Results P8 mice presented a dramatic decrease in Rcor2 gene expression compared with R1 controls in splenocytes, an alteration also observed in the brain cortex, hippocampus and primary astrocytes of these mice. Rcor2 reduction in astrocytes was accompanied by an increased basal expression of the interleukin (Il)-6 gene. Strikingly, intraperitoneal LPS injection in R1 mice downregulated Rcor2 in the hippocampus, with a concomitant upregulation of tumor necrosis factor (Tnf-α), Il1-β and Il6 genes. A negative correlation between Rcor2 and Il6 gene expression was also verified in LPS-treated C6 glioma cells. Knock down of Rcor2 by siRNA transfection (siRcor2) in R1 astrocytes upregulated Il6 gene expression while siRcor2 further increased Il6 expression in P8 astrocytes. Moreover, LPS activation provoked a further downregulation of Rcor2 and an amplified induction of Il6 in siRcor2-tranfected astrocytes. Conclusions Data presented here show interplay between Rcor2 downregulation and increased inflammation and suggest that Rcor2 may be a key regulator of inflammaging.
    Journal of Neuroinflammation 07/2014; 11(1):126. DOI:10.1186/1742-2094-11-126 · 4.90 Impact Factor
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    • "Antimicrobial peptides also frequently function as “alarmins”, triggering recruitment and activation of immune cells [10]. βA peptides are also pro-inflammatory, triggering activation of glial cells and macrophages, and this is thought to relate to neuronal injury [11]. Activation of glial cells by βA has been found to be mediated by TLR2 [12]. "
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    ABSTRACT: Accumulation of β-Amyloid (βA) is a key pathogenetic factor in Alzheimer's disease; however, the normal function of βA is unknown. Recent studies have shown that βA can inhibit growth of bacteria and fungi. In this paper we show that βA also inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro. The 42 amino acid fragment of βA (βA42) had greater activity than the 40 amino acid fragment. Direct incubation of the virus with βA42 was needed to achieve optimal inhibition. Using quantitative PCR assays βA42 was shown to reduce viral uptake by epithelial cells after 45 minutes and to reduce supernatant virus at 24 hours post infection. βA42 caused aggregation of IAV particles as detected by light transmission assays and electron and confocal microscopy. βA42 did not stimulate neutrophil H2O2 production or extracellular trap formation on its own, but it increased both responses stimulated by IAV. In addition, βA42 increased uptake of IAV by neutrophils. βA42 reduced viral protein synthesis in monocytes and reduced IAV-induced interleukin-6 production by these cells. Hence, we demonstrate for the first time that βA has antiviral activity and modulates viral interactions with phagocytes.
    PLoS ONE 07/2014; 9(7):e101364. DOI:10.1371/journal.pone.0101364 · 3.23 Impact Factor
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    • "Based on these data, they argued that TLR2 acts as an endogenous receptor for Aβ clearance, suggesting a beneficial role of TLR2 in AD. Anyhow, later studies showed that microglial TLR2 activation by Aβ peptide induces strong inflammatory activation [48, 49], which may be potentially harmful in vivo. Anyhow, it is clear that TLR2 on microglia function as a receptor for fibrillary Aβ peptide, and thereby regulates neuroinflammation during AD. "
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    ABSTRACT: Toll-like receptors (TLRs) belong to a class of pattern recognition receptors that play an important role in host defense against pathogens. TLRs on innate immune cells recognize a wide variety of pathogen-associated molecular patterns (PAMPs) and trigger innate immune responses. Later, it was revealed that the same receptors are also utilized to detect tissue damage to trigger inflammatory responses in the context of non-infectious inflammation. In the nervous system, different members of the TLR family are expressed on glial cells including astrocytes, microglia, oligodendrocytes, and Schwann cells, implicating their putative role in innate/inflammatory responses in the nervous system. In this regard, we have investigated the function of TLRs in neuroinflammation. We discovered that a specific member of the TLR family, namely TLR2, functions as a master sentry receptor to detect neuronal cell death and tissue damage in many different neurological conditions including nerve transection injury, intracerebral hemorrhage, traumatic brain injury, and hippocampal excitotoxicity. In this review, we have summarized our research for the last decade on the role of TLR2 in neuroinflammation in the above neurological disorders. Our data suggest that TLR2 can be an efficient target to regulate unwanted inflammatory response in these neurological conditions.
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