Anti-neuroinflammatory and Neuroprotective Effects of T-006 on Alzheimer's Disease Models by Modulating TLR4-Mediated MyD88/ NF-κB Signaling

Haiyun Chen; Xiao Chang; Jiemei Zhou; Guiliang Zhang; Jiehong Cheng; Zaijun Zhang; Jieyu Xing; Chunyan Yan; Zheng Liu

doi:10.2174/0118715273337232241121113048

Anti-neuroinflammatory and Neuroprotective Effects of T-006 on Alzheimer's Disease Models by Modulating TLR4-Mediated MyD88/ NF-κB Signaling

CNS Neurol Disord Drug Targets. 2025 Jan 8. doi: 10.2174/0118715273337232241121113048. Online ahead of print.

Authors

Haiyun Chen¹, Xiao Chang¹, Jiemei Zhou¹, Guiliang Zhang², Jiehong Cheng², Zaijun Zhang², Jieyu Xing¹, Chunyan Yan¹, Zheng Liu³

Affiliations

¹ School of Pharmacy, Clinical Pharmacy (School of Integrative Pharmacy), Guangdong Pharmaceutical University, Guangzhou, 510006, China.
² Institute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Guangzhou, 510632, China.
³ School of Medicine, Foshan University, Foshan, 528000, China.

PMID: 39791155
DOI: 10.2174/0118715273337232241121113048

Abstract

Introduction: Neuroinflammation derived from the activation of the microglia is considered a vital pathogenic factor of Alzheimer's Disease (AD). T-006, a tetramethylpyrazine derivative, has been found to alleviate cognitive deficits via inhibiting tau expression and phosphorylation in AD transgenic mouse models. Recently, T-006 has been proven to dramatically decrease the levels of total Amyloid β (Aβ) peptide and Glial Fibrillary Acidic Protein (GFAP) and suppress the expression of ionized calcium binding adaptor molecule-1 (Iba-1) in APP/PS1 mice. Therefore, we have further investigated the effects of T-006 on neuroinflammation in AD-like pathology.

Methods: The anti-inflammatory effects of T-006 and its underlying mechanisms were evaluated in Lipopolysaccharide (LPS)-induced AD rats. The potential protective effects against LPS-activated microglia-mediated neurotoxicity were also measured.

Results: T-006 significantly improved the cognitive impairment in LPS-induced AD rats by inhibiting the microglia/astrocyte activation. Further cellular assays found that T-006 significantly reserved the anomalous elevation of inflammatory cytokines in LPS-induced BV2 microglial cells in a concentration-dependent manner, while T-006 treatment alone showed no effects on the normal cultured cells. T-006 also reduced the levels of Toll-like Receptor 4 (TLR4)/Myeloid Differentiation protein-88 (MyD88)/NF-κB signaling-related proteins in BV2 cells exposed to LPS stimulation. TAK242, which selectively inhibits TLR4, slightly lessened the effects of T-006 in LPS-treatment BV2 cells without significance. Importantly, T-006 protected neurons against LPS-induced neuroinflammation by inhibiting the Reactive Oxygen Species (ROS) production and maintaining mitochondrial function.

Conclusion: T-006 inhibited TLR4-mediated MyD88/NF-κB signaling pathways to suppress neuroinflammation in the LPS-induced AD rat model.

Keywords: Alzheimer's disease.; MyD88/NF-κB signaling pathways; T-006; TLR4; Tetramethylpyrazine derivative; microglial activation; neuroinflammation.