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Li, B, Zhong, L, Yang, X, Andersson, T, Huang, M and Tang, SJ (2011) WNT5A signaling contributes to Aβ-induced neuroinflammation and neurotoxicity. PLoS ONE 6:e22920
Neurodegenration is a pathological hallmark of Alzheimer's disease (AD), but the underlying molecular mechanism remains elusive. Here, we present evidence that reveals a crucial role of Wnt5a signaling in this process. We showed that Wnt5a and its receptor Frizzled-5 (Fz5) were up-regulated in the AD mouse brain, and that beta-amyloid peptide (Aβ), a major constituent of amyloid plaques, stimulated Wnt5a and Fz5 expression in primary cortical cultures; these observations indicate that Wnt5a signaling could be aberrantly activated during AD pathogenesis. In support of such a possibility, we observed that inhibition of Wnt5a signaling attenuated while activation of Wnt5a signaling enhanced Aβ-evoked neurotoxicity, suggesting a role of Wnt5a signaling in AD-related neurodegeneration. Furthermore, we also demonstrated that Aβ-induced neurotoxicity depends on inflammatory processes, and that activation of Wnt5a signaling elicited the expression of proinflammatory cytokines IL-1β and TNF-α whereas inhibition of Wnt5a signaling attenuated the Aβ-induced expression of the cytokines in cortical cultures. Our findings collectively suggest that aberrantly up-regulated Wnt5a signaling is a crucial pathological step that contributes to AD-related neurodegeneration by regulating neuroinflammation.
Alzheimer Disease/genetics; Alzheimer Disease/metabolism; Amyloid beta-Peptides/genetics; Amyloid beta-Peptides/metabolism; Amyloid beta-Peptides/pharmacology; Amyloid beta-Protein Precursor/genetics; Amyloid beta-Protein Precursor/metabolism; Animals; Blotting, Western; Cell Survival/drug effects; Cells, Cultured; Hippocampus/metabolism; Hippocampus/pathology; Humans; Hydrogen Peroxide/pharmacology; Immunohistochemistry; Interleukin-1beta/metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons/drug effects; Neurons/metabolism; Neurotoxicity Syndromes/genetics; Neurotoxicity Syndromes/metabolism; Oxidants/pharmacology; Peptide Fragments/genetics; Peptide Fragments/metabolism; Peptide Fragments/pharmacology; Recombinant Proteins/metabolism; Recombinant Proteins/pharmacology; Signal Transduction/drug effects; Tumor Necrosis Factor-alpha/metabolism; Wnt Proteins/genetics; Wnt Proteins/metabolism; Wnt Proteins/pharmacology; Wnt-5a Protein