Dimethyl Itaconate Reduces Cognitive Impairment and Neuroinflammation in APPswe/PS1ΔE9 Transgenic Mouse Model of Alzheimer’s Disease

Xiong, Jing; Lu, Dong-Lin; Chen, Bai-Qiang; Liu, Tong-Yun; Wang, Zi-Xuan

doi:10.1007/s12017-022-08725-y

Cited by 14 publications

(9 citation statements)

References 33 publications

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“…The idea is consistent with the observed lack of substantial intracellular lipid accumulation, respiration, or ROS buildup upon prolonged palmitate exposure. Such substrate release could mediate the learning and memory effects that accompany aMMR; they are consistent with the data of other studies that have examined metabolite associations with learning and memory [44][45][46][47].…”

Section: Discussionsupporting

confidence: 89%

An acute microglial metabolic response controls metabolism and improves memory

Drougard

Eric

Wegert

et al. 2023

Preprint

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Chronic high-fat feeding triggers widespread metabolic dysfunction including obesity, insulin resistance, and diabetes. While these ultimate pathological states are relatively well understood, we have a limited understanding of how high-fat intake first triggers physiological changes. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on spatial and learning memory. Acute high-fat intake increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation, fission and metabolic skewing towards aerobic glycolysis. These effects are generalized, detectable in the hypothalamus, hippocampus, and cortex all within 1-3 days of HFD exposure. In vivo microglial ablation and conditional DRP1 deletion experiments show that the microglial metabolic response is necessary for the acute effects of HFD. 13C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate towards anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuro-protective metabolite itaconate. Together, these data identify microglial cells as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons instead as alternate bioenergetic and protective substrates. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.

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Section: Discussionsupporting

confidence: 89%

An acute microglial metabolic response controls metabolism and improves memory

Drougard

Eric

Wegert

et al. 2023

Preprint

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“…Our data provide a clue that DI may be disease-modifying drug for T. gondii -related neurodegenerative diseases. Notably, two recent studies supported that DI can alleviate neuroinflammation ( 46 ), and attenuate memory impairment in the mice model of AD ( 47 ). In future, clinical trials and mechanistic investigations should be further performed to demonstrate the therapeutic value of DI in neurodegenerative diseases including T. gondii -related cognitive deficits.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the derivatives of itaconate, such as Dimethyl itaconate (DI), have attracted extensive interests in the treatment of inflammatory diseases (36,(39)(40)(41)(42)(43)(44)(45). In addition, recent studies showed that DI can ameliorate neuroinflammation in a mouse model of multiple sclerosis (46), and can attenuate memory impairment in the mice model of AD (47). Here we were interested in whether the Acod1/itaconate axis has a protective effect in T. gondii-induced cognitive decline.…”

Section: Introductionmentioning

confidence: 99%

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

Yan

et al. 2022

Front. Immunol.

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BackgroundNeurodegenerative 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. MethodsA chronic T. gondii-infected mice (C57BL/6J) model was established via administration of cysts by gavage. Novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests were used to evaluate the behavior performance. Transmission electron microscopy, immunofluorescence, RT-PCR, western-blotting and RNA sequencing were utilized to determine the pathological changes, neuroinflammation and transcription profile in hippocampus tissues post infection, respectively. Moreover, the protective effect of Acod1/itaconate axis in T. gondii-induced cognitive deficits was evaluated.ResultsWe found that the latent infection of the parasite impaired the cognitive function, which was assessed behaviorally by novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests. 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 significantly ameliorate the cognitive deficits induced by T. gondii, which was proved by improvement of behavior performance and synaptic ultrastructure impairment, and lower accumulation of pro-inflammatory microglia. Notably, DI administration had a potential therapeutic effect on the cognitive deficits and synaptic impairment induced by the parasitic infection.ConclusionsOverall, 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.

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“…Long-term experimental results proved that mitochondria are the critical factors in the early induction and regulation of apoptosis Weber Boutros et al, 2022). Apoptotic stimuli such as DNA damage, ROS, or Fas signals mediate the death of mitochondrial cells by causing the release of small pro-apoptotic proteins generally located in the intermembrane space of the mitochondria, as shown in Figure 5 (Xiong et al, 2022). Once in the cytoplasm, proapoptotic proteins such as Cytochrome c (Cyt c), mitochondrialderived second caspase activator/low-PI direct IAP binding protein (Smac/Diablo), AIF, and endonuclease G trigger caspasedependent or independent apoptotic death pathways.…”

Section: Inhibition Of Neuronal Apoptosismentioning

confidence: 99%

Effect and mechanism of acupuncture on Alzheimer’s disease: A review

Dong

Zhu

et al. 2023

Front. Aging Neurosci.

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With the development trend of an aging society, Alzheimer’s disease (AD) has become an urgent problem in the field of medicine worldwide. Cognitive impairment in AD patients leads to a decline in the ability to perform daily living and abnormalities in behavior and personality, causing abnormal psychiatric symptoms, which seriously affect the daily life of patients. Currently, mainly drug therapy is used for AD patients in the clinic, but a large proportion of patients will experience drug efficacy not working, and even some drugs bring severe sleep disorders. Acupuncture, with its unique concept and treatment method, has been validated through a large number of experiments and proved its reliability of acupuncture in the treatment of AD. Many advances have been made in the study of the neurobiological mechanisms of acupuncture in the treatment of AD, further demonstrating the good efficacy and unique advantages of acupuncture in the treatment of AD. This review first summarizes the pathogenesis of AD and then illustrates the research progress of acupuncture in the treatment of AD, which includes the effect of acupuncture on the changes of biochemical indicators in AD in vivo and the specific mechanism of action to exert the therapeutic effect. Changes in relevant indicators of AD similarly further validate the effectiveness of acupuncture treatment. The clinical and mechanistic studies of acupuncture in the treatment of AD are intensified to fit the need for social development. It is believed that acupuncture will achieve new achievements in the treatment of AD as research progresses.

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Dimethyl Itaconate Reduces Cognitive Impairment and Neuroinflammation in APPswe/PS1ΔE9 Transgenic Mouse Model of Alzheimer’s Disease

Cited by 14 publications

References 33 publications

An acute microglial metabolic response controls metabolism and improves memory

An acute microglial metabolic response controls metabolism and improves memory

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

Effect and mechanism of acupuncture on Alzheimer’s disease: A review

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