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.
Alzheimer’s disease (AD) is the leading cause of dementia, with no effective therapies to reduce this progressive form of nerve cell death. Peptide thymosin β4 (Tβ4) controls actin polymerization and showed reduced neuroinflammation in middle stage AD model mice. To report the effect and mechanism of Tβ4 in early stage of AD model mice, Tβ4 overexpression or knockdown in 4 months APP/PS1 mice brain was achieved by genetic engineering methods. Two months later, behavioral test, electroencephalogram (EEG) test, immunofluorescence, immunohistochemistry, immunoblotting, dot blot, RT-PCR and transmission electron microscopy (TEM) were applied. The findings showed that the overexpression of Tβ4 displayed reduced microglia and astrocytes activation, arrested neuronal degeneration, repaired myelin sheath degeneration, decreased NF-κBp65 protein level, and restored EEG abnormality. Conversely, knockdown of Tβ4 led to lysosomal dysfunction, neuronal function weakening, myelin sheath loss, increased NF-κBp65 protein level, and further impaired image discrimination or spatial (working) memory in the APP/PS1 mice. The combination of TLR4 antagonist or NF-κBp65 inhibitor further reduced the inflammatory protein level. gv971 significantly reduced the glial reactivity and improved the neuronal survival, but not the learning and memory impairment of APP/PS1 mice. Combining Tβ4 with other therapies may be an effective strategy to combat the complex changes in AD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.