Using the Metabolome to Understand the Mechanisms Linking Chronic Arsenic Exposure to Microglia Activation, and Learning and Memory Impairment

Zhang, Rui-Yuan; Tu, Jie-Bai; Ran, Rui-Tu; Zhang, Wenxuan; Tan, Qiang; Tang, Ping; Kuang, Tao; Cheng, Shuqun; Chen, Chengzhi; Jiang, Xuejun; Han, Ting‐Li; Zhang, Ting; Cao, Xin; Peng, Bin; Zhang, Hua; Xia, Yinyin

doi:10.1007/s12640-020-00286-x

Cited by 18 publications

(8 citation statements)

References 67 publications

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“…The involvement of microglia in learning and memory has been reported in multiple studies, with majority of these studies reporting a negative role of microglia in learning and memory under inflammation and pathological conditions (Feng et al, 2019;Li et al, 2020b;Mohammadi et al, 2020;Worthen et al, 2020;Xie et al, 2020;Zhang et al, 2020a;Liao et al, 2021). Here we review three recent studies showing the specific role of microglia in memory quality (i.e.…”

Section: Microglia and Learning And Memorymentioning

confidence: 91%

Microglia regulation of synaptic plasticity and learning and memory

Cornell¹,

Salinas²,

Huang³

et al. 2022

Neural Regen Res

245

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Microglia are the resident macrophages of the central nervous system. Microglia possess varied morphologies and functions. Under normal physiological conditions, microglia mainly exist in a resting state and constantly monitor their microenvironment and survey neuronal and synaptic activity. Through the C1q, C3 and CR3 “Eat Me” and CD47 and SIRPα “Don’t Eat Me” complement pathways, as well as other pathways such as CX3CR1 signaling, resting microglia regulate synaptic pruning, a process crucial for the promotion of synapse formation and the regulation of neuronal activity and synaptic plasticity. By mediating synaptic pruning, resting microglia play an important role in the regulation of experience-dependent plasticity in the barrel cortex and visual cortex after whisker removal or monocular deprivation, and also in the regulation of learning and memory, including the modulation of memory strength, forgetfulness, and memory quality. As a response to brain injury, infection or neuroinflammation, microglia become activated and increase in number. Activated microglia change to an amoeboid shape, migrate to sites of inflammation and secrete proteins such as cytokines, chemokines and reactive oxygen species. These molecules released by microglia can lead to synaptic plasticity and learning and memory deficits associated with aging, Alzheimer’s disease, traumatic brain injury, HIV-associated neurocognitive disorder, and other neurological or mental disorders such as autism, depression and post-traumatic stress disorder. With a focus mainly on recently published literature, here we reviewed the studies investigating the role of resting microglia in synaptic plasticity and learning and memory, as well as how activated microglia modulate disease-related plasticity and learning and memory deficits. By summarizing the function of microglia in these processes, we aim to provide an overview of microglia regulation of synaptic plasticity and learning and memory, and to discuss the possibility of microglia manipulation as a therapeutic to ameliorate cognitive deficits associated with aging, Alzheimer’s disease, traumatic brain injury, HIV-associated neurocognitive disorder, and mental disorders.

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Section: Microglia and Learning And Memorymentioning

confidence: 91%

Microglia regulation of synaptic plasticity and learning and memory

Cornell¹,

Salinas²,

Huang³

et al. 2022

Neural Regen Res

245

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“…Metabolomics is a powerful approach to detect, identify, and quantify small molecules (below 1 kDa) in biological tissues and has been broadly utilized in toxicological studies for biomarker discovery and potential mechanisms [ 17 , 18 ]. The metabolism of placenta reflects the physiological and pathological status of the maternal organism as well as changes in response to environmental stimulus, including toxins exposure [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Exposure to two-dimensional ultrathin Ti3C2 (MXene) nanosheets during early pregnancy impairs neurodevelopment of offspring in mice

Wen

et al. 2022

J Nanobiotechnol

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Background Two-dimensional ultrathin Ti3C2 (MXene) nanosheets have been extensively explored for various biomedical applications. However, safety issues and the effects of Ti3C2 on human health remain poorly understood. Results To explore the influence on foetal or offspring after exposure to Ti3C2 nanosheets, we established a mouse model exposed to different doses of Ti3C2 nanosheets during early pregnancy in this study. We found that Ti3C2 nanosheets had negligible effect on the reproductive ability of maternal mice, including average pregnancy days, number of new-borns, and neonatal weight, etc. Unexpectedly, abnormal neurobehavior and pathological changes in the cerebral hippocampus and cortex in adult offspring were observed following Ti3C2 nanosheet treatment. In further studies, it was found that Ti3C2 exposure led to developmental and functional defects in the placenta, including reduced area of labyrinth, disordered secretion of placental hormones, and metabolic function derailment. The long-chain unsaturated fatty acids were significantly higher in the placenta after Ti3C2 exposure, especially docosahexaenoic acid (DHA) and linoleic acid. The metabolic pathway analysis showed that biosynthesis of unsaturated fatty acids was upregulated while linoleic acid metabolism was downregulated. Conclusions These developmental and functional defects, particularly metabolic function derailment in placenta may be the cause for the neuropathology in the offspring. This is the first report about the effects of Ti3C2 nanosheet exposure on pregnancy and offspring. The data provides a better understanding of Ti3C2 nanosheets safety. It is suggested that future studies should pay more attention to the long-term effects of nanomaterials exposure, including the health of offspring in adulthood, rather than only focus on short-term effects, such as pregnancy outcomes. Metabolomics could provide clues for finding the prevention targets of the biological negative effect of Ti3C2 nanosheets. Graphical Abstract

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“…Previous studies have suggested that arsenic can cause damage and apoptosis of microglia. 5 To verify this conclusion, the viability of microglia cells was determined to investigate the effect of NaAsO 2 on microglia cells. CCK-8 test indicated a decreased cell viability in a concentration-dependent manner (0, 2, 4, 8, 16 μmol/L), with 48% reduction at 16 μmol/L (Figure 1(a)).…”

Section: Resultsmentioning

confidence: 99%

“…4 Various forms of arsenic, such as monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and NaAsO 2 , can breach the blood-brain barrier, accumulating in different parts of the brain, resulting in neurological diseases. 5 Several studies have confirmed that arsenic exposure could trigger neuronal apoptosis, interfere with neuronal cytoskeletal proteins 6 and increase the expression of inflammatory cytokines in astrocytes. 7 Notably, microglia regulate the development, homeostasis, and pathogen defense of the central nervous system, and inorganic arsenic (iAs) always shows more significant toxicity to microglia.…”

Section: Introductionmentioning

confidence: 99%

Cathepsin B mediates the lysosomal-mitochondrial apoptosis pathway in arsenic-induced microglial cell injury

Zhang

Jiang

et al. 2023

Hum Exp Toxicol

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Arsenic is a prevalent environmental pollutant that targets the nervous system of living beings. Recent studies indicated that microglial injury could contribute to neuroinflammation and is associated with neuronal damage. Nevertheless, the neurotoxic mechanism underlying the arsenic-induced microglial injury requires additional research. This study explores whether cathepsin B promotes microglia cell damage caused by NaAsO2. Through CCK-8 assay and Annexin V-FITC and PI staining, we discovered that NaAsO2 induced apoptosis in BV2 cells (a microglia cell line). NaAsO2 was verified to increase mitochondrial membrane permeabilization (MMP) and promote the generation of reactive oxygen species (ROS) through JC-1 staining and DCFDA assay, respectively. Mechanically, NaAsO2 was indicated to increase the expression of cathepsin B, which could stimulate pro-apoptotic molecule Bid into the activated form, tBid, and increase lysosomal membrane permeabilization by Immunofluorescence and Western blot assessment. Subsequently, apoptotic signaling downstream of increased mitochondrial membrane permeabilization was activated, promoting caspase activation and microglial apoptosis. Cathepsin B inhibitor CA074-Me could mitigate the damage of microglial. In general, we found that NaAsO2 induced microglia apoptosis and depended on the role of the cathepsin B-mediated lysosomal-mitochondrial apoptosis pathway. Our findings provided new insight into NaAsO2-induced neurological damage.

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Using the Metabolome to Understand the Mechanisms Linking Chronic Arsenic Exposure to Microglia Activation, and Learning and Memory Impairment

Cited by 18 publications

References 67 publications

Microglia regulation of synaptic plasticity and learning and memory

Microglia regulation of synaptic plasticity and learning and memory

Exposure to two-dimensional ultrathin Ti3C2 (MXene) nanosheets during early pregnancy impairs neurodevelopment of offspring in mice

Cathepsin B mediates the lysosomal-mitochondrial apoptosis pathway in arsenic-induced microglial cell injury

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