AUTHOR=He Yan , Xu Daxiang , Yan Ziyi , Wu Yongshuai , Zhang Yongsheng , Tian Xiaokang , Zhu Jinhang , Liu Zhuanzhuan , Cheng Wanpeng , Zheng Kuiyang , Yang Xiaoying , Yu Yinghua , Pan Wei 

TITLE=A metabolite attenuates neuroinflammation, synaptic loss and cognitive deficits induced by chronic infection of Toxoplasma gondii

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1043572

DOI=10.3389/fimmu.2022.1043572

ISSN=1664-3224

ABSTRACT=Neurodegenerative diseases including AD is currently one of intractable problems globally due to the insufficiency of intervention strategies. Long-term infection of Toxoplasma gondii (T. gondii) can induce cognitive impairment in hosts, which is closely implicated in the pathogenesis of neurodegenerative diseases. Aconitate decarboxylase 1 (ACOD1) and its produced metabolite itaconate (termed ACOD1/itaconate axis), have recently attracted extensive interests due to its anti-inflammatory role in macrophages. However, whether the axis can influence cognitive function remains unknown. This study investigated the effect of ACOD1/itaconate axis in T. gondii-induced cognitive deficits. We found that the latent infection of the parasitic impaired the hippocampus-dependent cognitive function, which was assessed behaviorally by object location, novel object recognition, Y-maze memory tests and nest building. RNA sequencing of hippocampus showed that the infection downregulated the expression of genes related to synaptic plasticity, transmission and cognitive behavior. To our attention, the infection robustly upregulated the expression of genes associated with pro-inflammatory responses, which was characterized by microglia activation and disorder of ACOD1/itaconate axis. Interestingly, administration of dimethyl itaconate (DI, an itaconate derivative with cell membrane permeability) could obviously ameliorate the hippocampus-dependent cognitive impairment induced by T. gondii, which was proved by improvement of behavior performance, compromised synaptic ultrastructure and lower accumulation of pro-inflammatory microglia. Notably, DI administration had a therapeutic effect on the cognitive deficits and synaptic impairment induced by the parasitic infection. Overall, these findings provide a novel insight for the pathogenesis of T. gondii-related cognitive deficits in hosts, and also provide a novel clue for the potential therapeutic strategies.