Dimethyl itaconate ameliorates the deficits of goal-directed behavior in Toxoplasma gondii infected mice

Author:

Wu YongshuaiORCID,Xu Daxiang,He Yan,Yan Ziyi,Liu Rundong,Liu Zhuanzhuan,He Cheng,Liu Xiaomei,Yu Yinghua,Yang Xiaoying,Pan WeiORCID

Abstract

BackgroundThe neurotrophic parasiteToxoplasma gondii(T.gondii) has been implicated as a risk factor for neurodegenerative diseases. However, there is only limited information concerning its underlying mechanism and therapeutic strategy. Here, we investigated the effects ofT.gondiichronic infection on the goal-directed cognitive behavior in mice. Moreover, we evaluated the preventive and therapeutic effect of dimethyl itaconate on the behavior deficits induced by the parasite.MethodsThe infection model was established by orally infecting the cysts ofT.gondii. Dimethyl itaconate was intraperitoneally administered before or after the infection. Y-maze and temporal order memory (TOM) tests were used to evaluate the prefrontal cortex-dependent behavior performance. Golgi staining, transmission electron microscopy, indirect immunofluorescence, western blot, and RNA sequencing were utilized to determine the pathological changes in the prefrontal cortex of mice.ResultsWe showed thatT.gondiiinfection impaired the prefrontal cortex-dependent goal-directed behavior. The infection significantly downregulated the expression of the genes associated with synaptic transmission, plasticity, and cognitive behavior in the prefrontal cortex of mice. On the contrary, the infection robustly upregulated the expression of activation makers of microglia and astrocytes. In addition, the metabolic phenotype of the prefrontal cortex post infection was characterized by the enhancement of glycolysis and fatty acid oxidation, the blockage of the Krebs cycle, and the disorder of aconitate decarboxylase 1 (ACOD1)-itaconate axis. Notably, the administration of dimethyl itaconate significantly prevented and treated the cognitive impairment induced byT.gondii, which was evidenced by the improvement of behavioral deficits, synaptic ultrastructure lesion and neuroinflammation.ConclusionThe present study demonstrates thatT.gondiiinfection induces the deficits of the goal-directed behavior, which is associated with neuroinflammation, the impairment of synaptic ultrastructure, and the metabolic shifts in the prefrontal cortex of mice. Moreover, we report that dimethyl itaconate has the potential to prevent and treat the behavior deficits.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Jiangsu Province

Training Programs of Innovation and Entrepreneurship for College Students in Jiangsu Province

Publisher

Public Library of Science (PLoS)

Subject

Infectious Diseases,Public Health, Environmental and Occupational Health

Reference77 articles.

1. The cost of Alzheimer’s disease in China and re-estimation of costs worldwide.;J Jia;Alzheimers Dement.,2018

2. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures;JL Cummings;Alzheimers Res Ther,2014

3. Toxoplasmosis.;JG Montoya;Lancet,2004

4. Toxoplasmosis in pregnancy.;M Ahmed;Eur J Obstet Gynecol Reprod Biol,2020

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3