Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease

• Published in: The Journal of immunology (1950) 2008-11, Vol.181 (10), p.7254-7262
• Main Authors: Jana, Malabendu, Palencia, Carlos A, Pahan, Kalipada
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - immunology; Alzheimer Disease - metabolism; Amyloid beta-Peptides - immunology; Amyloid beta-Peptides - metabolism; Animals; Antigens, CD - biosynthesis; Cytokines - biosynthesis; Fluorescent Antibody Technique; Gene Expression; Gene Expression Profiling; Mice; Mice, Knockout; Microglia - immunology; Microglia - metabolism; Myeloid Differentiation Factor 88 - immunology; Myeloid Differentiation Factor 88 - metabolism; Peptide Fragments - immunology; Peptide Fragments - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 2 - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.10.7254

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.