Elsevier

Neuroscience Research

Volume 172, November 2021, Pages 73-79
Neuroscience Research

Chitotriosidase attenuates brain inflammation via HDAC3/NF-κB pathway in D-galactose and aluminum-induced rat model with cognitive impairments

https://doi.org/10.1016/j.neures.2021.05.014Get rights and content

Highlights

  • CHIT1 regulates brain inflammation via HDAC3/NF-κB p65 pathway, contributing to improvement of cognitive impairment.

  • CHIT1 skews polarization from a pro-inflammatory environment toward an anti-inflammatory one.

  • CHIT1 has a potential therapeutic value in AD via modulation of inflammation.

Abstract

Chitotriosidase (CHIT1, chitinase 1) is increased in the cerebrospinal fluid and peripheral blood of Alzheimer’s disease (AD) patients. Our previous study has shown that CHIT1 provides potential protection through microglial polarization and reduction of β-amyloid (Aβ) oligomers on rat models of AD. Histone deacetylase 3 (HDAC3) plays a significant role in the expression and regulation of proteins related to the pathophysiology of AD. In addition, nuclear factor-kappa B (NF-κB) signaling pathway activation in neurons is associated with the progression of AD. NF-κB activation is regulated by HDAC3 deacetylation. In the present study, we researched the role of CHIT1 in HDAC3/NF-κB signaling in D-galactose (D-gal) and aluminum-exposed rat model with cognitive impairments. Following CHIT1 treatment, we found that the protein and mRNA levels of HDAC3 and NF-κB were reduced, the expression level of IκBα increased, anti-inflammatory factors (Arg-1, IL-10, and CD206) were elevated while pro-inflammatory factors (TNF-a, iNOS, and IL-1β) were decreased in D-gal/aluminum-induced AD rats. These results indicate that CHIT1 can regulate brain inflammation via HDAC3/NF-κB p65 pathway, contributing to improvement of cognitive impairment.

Introduction

Alzheimer's disease (AD) is the most common neurodegenerative disease, whose etiology and pathogenesis are unknown (Vasefi et al., 2019). The main pathological discovery of AD contain Aβ plaques, tau tangles, synaptic degradation, and neuronal loss (Magalingam et al., 2018). Recently, microglia-associated inflammation becomes an important target in AD mechanisms. Microglia have different cellular phenotypes at different phases of the disease and play different roles in AD progression. Typically, microglia are divided into M1 type and M2 type. The former secretes TNF-α, IL-1, ROS, etc., which can promote inflammation while resulting in neurotoxic damage. The latter secretes Arg1, neurotrophic factors, etc., inhibits the inflammatory responses and promotes tissue repair (Tang and Le, 2016).

Chitotriosidase (CHIT1), located in chromosome 1q31-q32, is a member of the mammalian chitinase family and is synthesized and secreted by specifically activated macrophages/microglia (Barone et al., 2007; Olsson et al., 2012; Malaguarnera, 2006). CHIT1 was first described in plasma from patients with Gaucher disease (Hollak et al., 1994). Significant changes in CHIT1 expression were found at sites of inflammation, remodeling, and fibrosis (Pesce et al., 2006; Migliaccio et al., 2008). Increased levels of the enzyme have been detected in the cerebrospinal fluid and peripheral blood of AD patients (Di Rosa et al., 2006; Watabe-Rudolph et al., 2012). Previous research by our team has found that CHIT1 potentially plays a protective role against AD by polarizing microglia to an M2 phenotype and resisting Aβ oligomer deposition (Xiao et al., 2017). However, the signaling pathway which corresponds to the underlying mechanism of CHIT1 in AD is still unknown.

Histone deacetylase 3 (HDAC3) is a subtype of HDACs and has been found to be a critical negative regulator of long-term memory formation (McQuown et al., 2011). Inhibitors of HDACs have been shown to suppress the expression of pro-inflammatory factors such as TNF-α, IL-1β, etc., and further to improve neural function in cerebral infarction (Qi et al., 2004; Faraco et al., 2006). HDAC3-selective inhibitors demonstrate anti-inflammatory properties on macrophages by attenuating nuclear factor-kappa B (NF-κB) p65 transcriptional activity (Leus et al., 2016). Moreover, research shows that the inhibitor of HDAC3 suppresses the induction of inflammatory cytokines in rat models of acute liver failure by modulating the acetylation of NF-κB (Zhang et al., 2015). Recently, it is reported that specific inhibition of HDAC3 reversed the pathological changes of AD both in vitro and in a mouse model of AD (Janczura et al., 2018).

Considering both CHIT1 and HDAC3/NF-κB contribute to inflammation, we suspected that CHIT1 might be the upstream of HDAC3/NF-κB in AD-brain. Therefore, we designed the present study to supply the evidence that CHIT1 regulates brain inflammation via HDAC3 and NF-κB pathway.

Section snippets

Animal models

Adult male Sprague-Dawley rats (3 months old, weighing 300−320 g) were purchased from the Animal Center of Chongqing Medical University (Chongqing, China). Water and food were readily available to the rats throughout the experiment. Conditions were controlled as follows: temperature, 25 ± 1 °C; humidity, 50 ± 10 %; and light, 12-h light/dark cycle. All experiments had approval from the Experimental Animal Ethics Committee of Chongqing Medical University.

The subacute model of AD induced by D-gal

CHIT1 intervention made cognitive function of subacute AD model rats changed

In order to assess the cognitive function of rats, we performed MWM test. In the place navigation trial, the escape latency of the AD model group was considerably longer than that of the control group (p < 0.05) (Fig. 1a). In addition, the escape latency of the AD model group treated with CHIT1 was significantly shorter than that of the AD model rats (p < 0.05), while the escape latency of the AD model group treated with CHIT1 inhibitor (CHIT1-IN-2) was significantly longer than CHIT1 treatment

Discussion

In the present study, we demonstrate that CHIT1 ameliorates the cognitive impairment by modulation of brain inflammation via HDAC3/NF-κB pathway. To our knowledge, this is the first time to provide evidence that CHIT1 promote brain anti-inflammatory environment via HDAC3/NF-κB signaling.

Our previous study indicates that CHIT1 provides potential protection through microglial polarization and reduction of Aβ oligomers in D-gal and AlCl3-induced rat model with cognitive impairments (Xiao et al.,

Conclusions

In conclusion, our study indicates that CHIT1 reduces brain inflammation the HDAC3/NF-κB p65 pathway in AD, and this study also highlights the importance of epigenetics in AD. In addition, our experiment also helped to elucidate the mechanism of action of CHIT1.

Author contributions

Xingyan Yu and Yang Lü designed the experiments. Xingyan Yu, Weihua Yu, Lihua Wu and Wenkai Yang performed the experiments and analyzed all data. Xingyan Yu drafted the manuscript. Yang Lü revised the manuscript.

Funding

This study was supported by grants from Chongqing Natural Science Foundation (cstc2018jcyjAX0169).

Declaration of Competing Interest

The authors report no declarations of interest.

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