Iribarren, P. et al. CpG-containing oligodeoxynucleotide promotes microglial cell uptake of amyloid 1-42 peptide by upregulating the expression of the G-protein-coupled receptor mFPR2. FASEB J. 19, 2032-2034

Laboratory of Molecular Immunoregulation, NCI-Frederick, Фредерик, Maryland, United States
The FASEB Journal (Impact Factor: 5.04). 01/2006; 19(14):2032-4. DOI: 10.1096/fj.05-4578fje
Source: PubMed


Human G protein-coupled formyl peptide receptor like 1 (FPRL1) and its mouse homologue murine formyl peptide receptor 2 (mFPR2) mediate the chemotactic activity of amyloid beta 1-42 (Abeta42), a key pathogenic peptide in Alzheimer's disease (AD). Since mFPR2 is up-regulated in mouse microglia by lipopolysaccharide (LPS), a Toll-like receptor 4 ligand, we investigated the capacity of CpG-containing oligodeoxynucleotide (ODN), a Toll-like receptor (TLR) 9 ligand, to regulate the expression of mFPR2 in mouse microglia. CpG ODN markedly enhanced the expression and function of mFPR2 in microglial cells, which exhibited increased chemotactic responses to mFPR2 agonists, including Abeta42. The effect of CpG ODN is dependent on activation of p38 MAPK. Further studies showed that CpG ODN-treated microglia increased their capacity to endocytose Abeta42 through mFPR2, as this process was abrogated by pertussis toxin, a Gi protein inhibitor, and W peptide, another potent mFPR2 agonist. Our results suggest that TLR9 may play an important role in promoting microglial recognition of Abeta42, thus affecting the pathogenic process of AD.

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    • "Senescence of microglia function has been suggested to play a fundamental role in both AD and other neurodegenerative diseases [28,76]. Prior studies have also shown that microglia become significantly more efficient at Aβ uptake and degradation when stimulated with TLR agonists in vitro [77,78]. It has been reported that activation of microglia with TLR agonists can induce acidification of lysosomes, allowing efficient degradation of Aβ [75]. "
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    ABSTRACT: Alzheimer¿s disease (AD) is the most common cause of dementia, and currently, there is no effective treatment. The major neuropathological lesions in AD are accumulation of amyloid ß (Aß) as amyloid plaques and congophilic amyloid angiopathy, as well as aggregated tau in the form of neurofibrillary tangles (NFTs). In addition, inflammation and microglia/macrophage function play an important role in AD pathogenesis. We have hypothesized that stimulation of the innate immune system via Toll-like receptor 9 (TLR9) agonists, such as type B CpG oligodeoxynucleotides (ODNs), might be an effective way to ameliorate AD related pathology. We have previously shown in the Tg2576 AD model that CpG ODN can reduce amyloid deposition and prevent cognitive deficits. In the present study, we used the 3xTg-AD mice with both Aß and tau related pathology. The mice were divided into 2 groups treated from 7 to 20 months of age, prior to onset of pathology and from 11 to 18 months of age, when pathology is already present. We demonstrated that immunomodulatory treatment with CpG ODN reduces both Aß and tau pathologies, as well as levels of toxic oligomers, in the absence of any apparent inflammatory toxicity, in both animal groups. This pathology reduction is associated with a cognitive rescue in the 3xTg-AD mice. Our data indicates that modulation of microglial function via TLR9 stimulation is effective at ameliorating all the cardinal AD related pathologies in an AD mouse model mice suggesting such an approach would have a greater chance of achieving clinical efficacy.
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    • "Activated microglia express surface molecules such as Fc receptor, CD11b, CD11c, CD14, major histocompatibility complex (MHC) molecules, Toll-like receptors (TLRs), scavenger receptors, and cytokine/chemokine receptors, and they can act as both antigen-presenting cells and immunological effector cells (Suzumura et al., 1987; Rock et al., 2004). In addition to innate immunity, activated microglia also play other beneficial roles, such as neuroprotection mediated by release of neurotrophic factors (Zietlow et al., 1999; Bessis et al., 2007; Liang et al., 2010), maintenance of CNS homeostasis by clearance of cellular debris and toxic substances (Upender and Naegele, 1999; Marin-Teva et al., 2004; Iribarren et al., 2005; Simard et al., 2006; Richard et al., 2008), and guidance of stem-cell migration in neuronal repair and neurogenesis (Aarum et al., 2003; Ziv et al., 2006a,b). "
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    ABSTRACT: Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g., minocycline) have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.
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    • "However, when a non-specific B cell or other APC encounters a CpG-antigen conjugate – which is probably a more common event in a physiological situation – has not been studied widely. Only indirect effects of CpG treatment on enhancement of microbe uptake by macrophages [9] or of amyloid ␤ 1–42 peptide by microglial cells [10] were reported. We have developed a modular system for experimental vaccination based on streptavidin (SA) as a model antigen and monobiotinylated targeting units. "
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    ABSTRACT: CpG oligodeoxynucleotides (CpG) are widely studied as promising adjuvants in vaccines against a range of diseases including infection, cancer or allergy. Conjugating antigen to CpG has been shown to potentiate the adjuvant effect via enhancing antigen uptake and danger signaling by the very same cell. In the present study, using biotinylated CpG and streptavidin as a model system, we demonstrate that CpG motif containing free and antigen-conjugated oligonucleotides do not compete in terms of cell activation via TLR9, but do compete for cellular uptake. Antigen-conjugated CpG enhances cellular association and uptake of the antigen by antigen-presenting cells (APC) and T cells. Free CpG efficiently competes with antigen-CpG conjugates in BMDC and T cells, but shows weak or no competition in B cells that have higher TLR9 expression. Vaccination with antigen-conjugated CpG or with a mixture of antigen and CpG elevates the level of antigen-specific antibodies but co-administration of CpG-antigen conjugates and free CpG adversely effects immunogenicity. These observations may help optimize CpG-based vaccine formulation.
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