Influence of thalamic IL-33 signaling in aging-associated exacerbation of cognitive impairment after brain injury via microglial dysfunction and tau pathology
丘脑 IL-33 信号传导通过小胶质细胞功能障碍和 tau 病理学对脑损伤后衰老相关认知障碍恶化的影响
基本信息
- 批准号:10525027
- 负责人:
- 金额:$ 145.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AgingAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAntibodiesAreaAstrocytesAttenuatedAutomobile DrivingBrainBrain InjuriesBrain imagingCSF1R geneCognitive deficitsDataDementiaEnvironmentFoundationsFrontotemporal DementiaFunctional disorderGene ExpressionGene Expression ProfileGenesHippocampus (Brain)HumanImpaired cognitionInjectionsInjuryInterleukinsLeadLinkLipidsLong-Term EffectsMediator of activation proteinMemory impairmentMicrogliaMolecular ProfilingMusNerve DegenerationNeuronal DysfunctionNeuronsOligodendrogliaPathologyProcessReportingRisk FactorsRoleSignal TransductionSiteSpinal cord injuryTNF geneTestingThalamic structureTherapeuticTraumatic Brain InjuryValidationage effectagedaging populationbasedesignexperimental studyimaging studyimprovedin vivoinjuredinjury recoverylipid metabolismmemory recognitionmiddle agemonocytemouse modelneuroimagingneutralizing antibodynovelpreventreceptorrecruitresponsesingle-cell RNA sequencingtau Proteinstau aggregationtau-1young adult
项目摘要
ABSTRACT
Traumatic brain injury is a risk factor for cognitive impairment and dementia, such as Alzheimer’s disease (AD)
and frontotemporal dementia (FTD), particularly in the aged populations. Nevertheless, the mechanisms by
which aging exacerbates cognitive deficits after brain injury are not fully understood. Human brain imaging
studies reported the signs of microglial activation in the thalamus that correlate with cognitive deficits. Our
preliminary studies using a local microglia depletion in mice have discovered that thalamic microglia activation
is required for cognitive deficits after brain injury. In the middle-aged mice, cognitive deficits after brain injury
were exacerbated and accompanied by dysregulated responses of microglia and accumulation of AT8-positive
phosphorylated tau proteins (p-tau). Recent studies have reported that one of the aging-associated molecular
signatures in the mouse brain is an increased interleukin-33 (IL-33) expression in oligodendrocytes. Indeed, IL-
33 expression was increased in thalamic oligodendrocytes. Notably, blocking of IL-33 in the aging thalamus
ameliorated aging-associated exacerbation of cognitive deficits. These findings suggest that aging-associated
changes in the thalamic environment and microglial responses contribute to p-tau accumulation and
exacerbated cognitive deficits in aged mice after cortical injuries. Thus, in the proposed study, we will test our
hypothesis that aging-associated oligodendrocyte-derived IL-33 exacerbates cognitive impairment
after cortical injury by driving microglial dysfunction and tau pathology in the thalamus. In Aim 1, we
will further evaluate aging-associated changes in thalamic pathology and cognitive impairment after cortical
injuries and determine the effects of thalamic microglial depletion and neuronal tau deletion on exacerbated
cognitive impairment. In Aim 2, we will investigate the requirement of oligodendrocyte-microglial IL-33
signaling in aging-associated microglial dysfunction, p-tau accumulation, and worsening cognitive impairment
after cortical injuries. In Aim 3, we will examine the mechanisms by which aging-associated IL-33 signaling
alters microglial responses after cortical injuries. Together, this study will determine the mechanisms by which
oligodendrocyte-microglia IL-33 signaling induces microglial dysfunction, p-tau accumulation, and cognitive
impairment relevant for AD/ADRD.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Shinichi Kano其他文献
Shinichi Kano的其他文献
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{{ truncateString('Shinichi Kano', 18)}}的其他基金
Requirement of astrocyte-derived immune signaling for the hippocampal-cortical circuit for social novelty recognition
海马皮质回路星形胶质细胞衍生的免疫信号对社交新奇识别的需求
- 批准号:
10527179 - 财政年份:2022
- 资助金额:
$ 145.3万 - 项目类别:
Requirement of astrocyte-derived immune signaling for the hippocampal-cortical circuit for social novelty recognition
海马皮质回路星形胶质细胞衍生的免疫信号对社交新奇识别的需求
- 批准号:
10657731 - 财政年份:2022
- 资助金额:
$ 145.3万 - 项目类别:
Impact of immune cell-derived exosomes and miRNAs on brain function and behavior
免疫细胞衍生的外泌体和 miRNA 对大脑功能和行为的影响
- 批准号:
9908179 - 财政年份:2018
- 资助金额:
$ 145.3万 - 项目类别:
Impact of immune cell-derived exosomes and miRNAs on brain function and behavior
免疫细胞衍生的外泌体和 miRNA 对大脑功能和行为的影响
- 批准号:
10083112 - 财政年份:2018
- 资助金额:
$ 145.3万 - 项目类别:
Impact of immune cell-derived exosomes and miRNAs on brain function and behavior
免疫细胞衍生的外泌体和 miRNA 对大脑功能和行为的影响
- 批准号:
10318178 - 财政年份:2018
- 资助金额:
$ 145.3万 - 项目类别:
Impact of immune cell-derived exosomes and miRNAs on brain function and behavior
免疫细胞衍生的外泌体和 miRNA 对大脑功能和行为的影响
- 批准号:
10381772 - 财政年份:2018
- 资助金额:
$ 145.3万 - 项目类别:
Role of Glia and Inflammation in Altered Synapse Development in Schizophrenia
神经胶质细胞和炎症在精神分裂症突触发育改变中的作用
- 批准号:
8323243 - 财政年份:2011
- 资助金额:
$ 145.3万 - 项目类别:
Role of glia and inflammation in altered synapse development in schizophrenia
神经胶质细胞和炎症在精神分裂症突触发育改变中的作用
- 批准号:
8836668 - 财政年份:2011
- 资助金额:
$ 145.3万 - 项目类别:
Role of Glia and Inflammation in Altered Synapse Development in Schizophrenia
神经胶质细胞和炎症在精神分裂症突触发育改变中的作用
- 批准号:
8091057 - 财政年份:2011
- 资助金额:
$ 145.3万 - 项目类别:














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