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. 2024 Oct:121:291-302.
doi: 10.1016/j.bbi.2024.08.002. Epub 2024 Aug 2.

TLR2 immunotherapy suppresses neuroinflammation, tau spread, and memory loss in rTg4510 mice

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Free article

TLR2 immunotherapy suppresses neuroinflammation, tau spread, and memory loss in rTg4510 mice

Youbin Kim et al. Brain Behav Immun. 2024 Oct.
Free article

Abstract

In Alzheimer's disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer's disease.

Keywords: Alzheimer’s disease; Microglial activation; OPN-305; Parahippocampal gyrus; Proinflammatory cytokines; Tau propagation; Tauopathy; Toll-like receptor 2; Tomaralimab.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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