2. Academic Validation
  3. Thymosin β4 reverses phenotypic polarization of glial cells and cognitive impairment via negative regulation of NF-κB signaling axis in APP/PS1 mice

Thymosin β4 reverses phenotypic polarization of glial cells and cognitive impairment via negative regulation of NF-κB signaling axis in APP/PS1 mice

  • J Neuroinflammation. 2021 Jun 28;18(1):146. doi: 10.1186/s12974-021-02166-3.
Meng Wang 1 2,  Li-Rong Feng 1 2,  Zi-Long Li 1 2,  Kai-Ge Ma 2 3 4,  Ke-Wei Chang 1 2 3,  Xin-Lin Chen 2 3 4,  Peng-Bo Yang 1 2 3,  Sheng-Feng Ji 1 2 3,  Yan-Bing Ma 1 2 3,  Hua Han 1 2 3,  John Bosco Ruganzua 1 2,  Wei-Na Yang 1 2 3,  Yi-Hua Qian 5 6 7
Affiliations

Affiliations

  • 1 Department of Human Anatomy and Histology-Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, Shaanxi, China.
  • 2 Institute of Neuroscience, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
  • 3 Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, Shaanxi, China.
  • 4 Institute of Neurobiology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
  • 5 Department of Human Anatomy and Histology-Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, Shaanxi, China. qianyh38@mail.xjtu.edu.cn.
  • 6 Institute of Neuroscience, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China. qianyh38@mail.xjtu.edu.cn.
  • 7 Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, Shaanxi, China. qianyh38@mail.xjtu.edu.cn.
PMID: 34183019 DOI: 10.1186/s12974-021-02166-3
Abstract

Background: Thymosin β4 (Tβ4) is the most abundant member of the β-thymosins and plays an important role in the control of actin polymerization in eukaryotic cells. While its effects in multiple organs and diseases are being widely investigated, the safety profile has been established in Animals and humans, currently, little is known about its influence on Alzheimer's disease (AD) and the possible mechanisms. Thus, we aimed to evaluate the effects and mechanisms of Tβ4 on glial polarization and cognitive performance in APP/PS1 transgenic mice.

Methods: Behavior tests were conducted to assess the learning and memory, anxiety and depression in APP/PS1 mice. Thioflavin S staining, Nissl staining, immunohistochemistry/immunofluorescence, ELISA, qRT-PCR, and immunoblotting were performed to explore Aβ accumulation, phenotypic polarization of glial cells, neuronal loss and function, and TLR4/NF-κB axis in APP/PS1 mice.

Results: We demonstrated that Tβ4 protein level elevated in all APP/PS1 mice. Over-expression of Tβ4 alone alleviated AD-like phenotypes of APP/PS1 mice, showed less brain Aβ accumulation and more Insulin-degrading Enzyme (IDE), reversed phenotypic polarization of microglia and astrocyte to a healthy state, improved neuronal function and cognitive behavior performance, and accidentally displayed antidepressant-like effect. Besides, Tβ4 could downregulate both TLR4/MyD88/NF-κB p65 and p52-dependent inflammatory pathways in the APP/PS1 mice. While combination drug of TLR4 Antagonist TAK242 or NF-κB p65 inhibitor PDTC exerted no further effects.

Conclusions: These results suggest that Tβ4 may exert its function by regulating both classical and non-canonical NF-κB signaling and is restoring its function as a potential therapeutic target against AD.

Keywords

Alzheimer’s disease; Cognition and emotion; NF-κB signaling pathway; Phenotypic polarization of glial cells and neuroinflammation; Thymosin β4.

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