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Fibrillar Amyloid-β Peptides Activate Microglia via TLR2: Implications for Alzheimer’s Disease¹

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612

Microglial activation is an important pathological component in brains of patients with Alzheimer’s disease (AD), and fibrillar amyloid-β (Aβ) peptides play an important role in microglial activation in AD. However, mechanisms by which Aβ peptides induce the activation of microglia are poorly understood. The present study underlines the importance of TLR2 in mediating Aβ peptide-induced activation of microglia. Fibrillar Aβ1–42 peptides induced the expression of inducible NO synthase, proinflammatory cytokines (TNF-, IL-1β, 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 Aβ1–42-induced expression of proinflammatory molecules and integrin markers in microglia. Aβ1–42 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 Aβ1–42 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 Aβ-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 Aβ1–42 peptide-induced expression of proinflammatory molecules. Taken together, these studies delineate a novel role of TLR2 signaling pathway in mediating fibrillar Aβ peptide-induced activation of microglia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by Grant IIRG-07-58684 from Alzheimer’s Association and Grants NS39940 and NS48923 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Suite 320, Chicago, IL 60612. E-mail address: Kalipada_Pahan{at}rush.edu

³ Abbreviations used in this paper: AD, Alzheimer’s disease; iNOS, inducible NO synthase; Aβ, amyloid-β; LTA, lipoteichoic acid; poly(I-C), polyinosinic-polycytidylic acid; ASO, antisense oligonucleotide; ScO, scrambled oligonucleotide.

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