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

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.

Microglia Polarization From M1 to M2 in Neurodegenerative Diseases

“…Electroacupuncture, a widely used Chinese traditional therapy, improved learning, and memory of AD rats, inhibited the activation of glia and polarized microglia toward M2 phenotype in hippocampus of AD rats with decreased pro-inflammatory cytokines and increased anti-inflammatory cytokines by inhibiting NF-κB pathway but activating STAT-6 pathway ( Xie et al, 2021 ). Over-expression of thymosin β4 (Tβ4), a constituent part of cytoplasm and cytoskeleton, improved neuronal function and cognitive ability, reduced brain Aβ accumulation, upregulated insulin-degrading enzyme, and alleviated neuroinflammatory response by converting microglia and astrocyte to neuroprotective phenotype in APP/PS1 mice via negative regulation of TLR4/MyD88/NF-κB p65 and p52 pathways ( Wang et al, 2021 ).…”

Gut microbiota may be involved in Alzheimer’s disease pathology by dysregulating pyrimidine metabolism in APP/PS1 mice

“…Cognitive deficit is a defining characteristic of AD. APP/PS1 mice are widely used in AD research ( Wang M. et al, 2021 ) because they model well the pathological changes of AD such as senile plaque, neuronal deletion, amyloid-associated inflammation and cognitive decline. It was shown that APP/PS1 mice developed learning and memory deficits at 6 months of age ( Webster et al, 2014 ), which is now considered to be the early stage of AD in this model.…”

Adiponectin attenuates splenectomy-induced cognitive deficits by alleviating neuroinflammation and oxidative stress via the TLR4/MyD88/NF-κb signaling pathway in aged rats

“…TLR4 agonists can activate MyD88-dependent intracellular signaling pathways, leading to the translocation of NF-κb. Phosphorylation of NF-κb results in its activation and translocation into the nucleus, where it mediates a series of downstream reactions, especially oxidative stress and neuroin ammation [37][38][39]. Phosphorylation of p65 is a marker of NF-κb activation.…”