Sodium butyrate ameliorates the impairment of synaptic plasticity by inhibiting the neuroinflammation in 5XFAD mice

Mar 31, 2021Chemico-biological interactions

Sodium butyrate improves brain cell connections by reducing brain inflammation in Alzheimer's model mice

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Abstract

Sodium butyrate (NaB) treatment improved synaptic plasticity in 5XFAD mice, which model early Alzheimer's disease.

In 5XFAD mice, treatment with NaB for 2 weeks reversed increases in pro-inflammatory cytokines associated with Alzheimer's disease.
NaB treatment led to more abundant dendritic spines compared to untreated AD mice, suggesting enhanced synaptic connections.
Long-term potentiation was promoted in 5XFAD mice after NaB treatment, indicating improved synaptic function.
NaB treatment reduced the over-activation of microglia and the accumulation of beta-amyloid, which are linked to neuroinflammation.
No significant behavioral differences were observed among the different treatment groups in novel object recognition and Morris water maze tests.

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Current strategies for the treatment of Alzheimer's disease (AD) focus on the pathology in the later stages of disease progression. Early microglia abnormality and β-amyloid (Aβ) deposition trigger disease development before identical symptoms emerge, which leads to poor clinical treatment effects in the later stages. In the early stage of disease progression, microglia in brains of 5XFAD mice have been activated by Aβ plaques to secrete more pro-inflammatory cytokines. In the meantime, these cytokines up-regulate Aβ via increasing the APP processing. Sodium butyrate (NaB), as one of the short chain fatty acid (SCFA) generated by gut microbiota, is the inhibitor of histone deacetylase (HDAC), which reduces the secretion of pro-inflammatory cytokines. In our experiment, 8-week-old 5XFAD mice and their litter WT mice were treated with NaB or normal saline for 2 weeks (WT + Vehicle group, WT + NaB group, AD + Vehicle group and AD + NaB group). After treatment, behavioral tests were carried out. The novel object recognition (NOR) and Morris water maze (MWM) tests demonstrated that there was no significant difference between four groups of mice. The results of long-term potentiation (LTP) and depotentiation (DEP) illustrated that the synaptic plasticity was promoted in 5XFAD mice after treatment with NaB. Compared to the AD + Vehicle group, the dendritic spines were more abundant in other groups of mice. Furthermore, the synapse-associated proteins (PSD-95, SYP, NR2B) were reduced and the pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were increased in the AD + Vehicle group. These phenomena were reversed after treatment with NaB. Moreover, our results suggested that NaB suppressed the over-activation of microglia and the accumulation of Aβ in AD mice. Altogether, all results illustrated that HDAC inhibitor NaB could ameliorate the synaptic plasticity by reducing neuroinflammation in 5XFAD mice in the early stage of the disease.

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Sodium butyrate ameliorates the impairment of synaptic plasticity by inhibiting the neuroinflammation in 5XFAD mice

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