Activation of the innate immune response by the Alzheimer's amyloid beta protein via toll-like receptors.

摘要

Alzheimer's Disease (AD) is the most common form of neurodegenerative disease characterized by the generation and deposition of amyloid beta plaques and the formation of neurofibrillary tangles. A wealth of data now demonstrate that inflammation is a prominent feature in AD pathology and a potential therapeutic target for the treatment and prevention of the disease. The emergence of evidence linking amyloid beta protein (Abeta), the primary component of senile plaques, to inflammation has led to new insights into understanding AD pathology. Abeta, a protein fragment resulting from cleavage of human amyloid precursor protein (APP), primarily exists in two forms: a slower-aggregating 40-amino acid long peptide (Abeta(1-40)), and a faster-aggregating 42-residue peptide Abeta(1-42). This investigation focused on elucidating the mechanism by which Abeta provokes an inflammatory response in AD. For this study, we utilized THP-1 human monocytes/macrophages as an inflammatory model system due to their sensitivity to Abeta. We hypothesized that fibrillar A(beta(1-42) may utilize Toll-like receptors (TLRs), a family of transmembrane receptors that mediate recognition of certain conserved structural motifs in pathogens, for production of proinflammatory products and activation of the innate immune response. Biophysical characterization of the bioactive species of Abeta(1-42) revealed that a soluble yet fibrillar species of Abeta(1-42) invokes tumor necrosis factor alpha (TNFalpha) production in THP-1 monocytes/macrophages. Moreover, using a TLR antibody neutralization assay, whereby receptor blockade inhibits cell responsiveness to TLR ligands, we showed that both TLR2 and TLR4 were highly involved in Abeta(1-42)-induced TNFalpha production. The role of TLR2 in Abeta-induced innate immune response was further substantiated by the production of proinflammatory interleukin-8 (IL-8) in transfected HEK293 cells, a mammalian cell line that does not express TLR2, after stimulation with Abeta(1-42). Furthermore, our results suggest the possible involvement of TLR2/TLR1 or TLR2/TLR6 for the Abeta-induced activation of TLR downstream signaling. Taken together, our findings provide strong correlation between Abeta and innate immune response activation via TLR2 and TLR4. The identification of TLRs that recognize Abeta has opened new venues for understanding the mechanism of Abeta-induced inflammatory response and may thus be a new therapeutic target for AD.