Toll-like receptors (TLRs), which have been implicated in various neuroinflammatory responses, are thought to act in defense mechanisms by inhibiting neuronal cell death in Alzheimer's disease. In this study, we evaluated the effects of TLR2 on amyloid beta peptide 25-35 (Aβ25-35)-induced neuronal cell death, synaptic dysfunction, and microglial activation in organotypic hippocampal slice cultures (OHSCs) from wild-type (WT) C57BL/6 mice and TLR2-knockout (KO) mice. In WT mice, Aβ25-35 induced β-amyloid aggregation and surrounding TLR2 expression. And, propidium iodide (PI) uptake, which is a measure of cell death, increased in a dose-dependent manner in slices with Aβ25-35 treatment. In the Aβ25-35-treated TLR2-KO OHSCs, the PI uptake was significantly attenuated to the control level, indicating that the cells were less susceptible to Aβ25-35-induced neuronal toxicity. In the ultrastructural analysis, nuclear shrinkage, slightly swollen mitochondria, and degraded organelles were detected in the Aβ25-35-treated slices from WT mice but not in the Aβ25-35-treated slices from TLR2-KO, suggesting the resistance of TLR2-KO to Aβ25-35-induced neurotoxicity. In Aβ25-35-treated OHSCs of WT mice, the levels of phosphorylated tau were increased and the levels of synaptophysin were decreased in a dose-dependent manner, but they were not changed in OHSCs of TLR2-KO mice. In WT mice, Aβ25-35 increased total protein level and immunoreactivity of Iba-1, which was colocalized with TLR2. However, there were no significant changes in the slices of Aβ25-35-treated TLR2-KO mice. These results suggested that TLR2 may play a role in Aβ25-35-induced neuronal cell loss and synaptic dysfunction through the activation of microglia in OHSCs.
Keywords: AD; Alzheimer’s disease; Aβ; Aβ(25–35)-induced neuronal loss; Microglia; OHSCs; Organotypic hippocampal slice cultures; PI; Synaptophysin; TLR2; TLR2-KO; Toll-like receptor 2; Toll-like receptor 2 (TLR2); Toll-like receptor 2-knockout; WT; amyloid beta peptide; organotypic hippocampal slice cultures; p-tau; propidium iodide; wild-type.
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