Microglia Activation and TLR-induced Neurodegeneration by Alcohol Promotes Progression of Alzheimer Pathology
酒精引起的小胶质细胞激活和 TLR 诱导的神经变性促进阿尔茨海默病病理学的进展
基本信息
- 批准号:10265596
- 负责人:
- 金额:$ 38.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-20 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:3xTg-AD mouseAgeAlcohol consumptionAlcoholsAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAmyloid beta-ProteinApolipoprotein EApoptosisApoptoticAutopsyBrainBrain DiseasesBrain regionCASP3 geneCell DeathCell NucleusChronicComplement 1qDementiaDiseaseEthanolGenesGenotypeGoalsHMGB1 geneHippocampus (Brain)HumanImpaired cognitionImpairmentIn Situ Nick-End LabelingIndividualInflammationInflammatoryLeadLifeLigandsLinkMeasurementMediatingMediator of activation proteinMemory impairmentMicroRNAsMicrogliaModelingMolecular ProfilingMusNerve DegenerationNeuroimmuneNeuronsNuclear RNAPathologicPathologyPhagocytesPhagocytosisPhenotypePrefrontal CortexProteinsReceptor ActivationRestReverse Transcriptase Polymerase Chain ReactionSenile PlaquesSignal TransductionSliceSmall Nuclear RNAStainsSynapsesTLR4 geneTLR7 geneTestingTherapeuticToll-like receptorsTumor Necrosis Factor ReceptorUp-RegulationWestern Blottingabeta depositionage relatedalcohol effectalcohol use disordercytokineearly alcohol usegene inductiongenome wide association studyin vivoinnovationlocomotor deficitmolecular pathologymolecular phenotypemouse modelneuron lossneurotoxicreceptorsynaptic pruningtau Proteinstau-1transcriptome sequencing
项目摘要
Abstract
Chronic heavy or binge alcohol use is associated with dementia and increased risk for Alzheimer's disease (AD),
though mechanisms connecting the disease pathologies have not been identified. AD pathology follows a
temporal progression of proinflammatory signaling in brain with Aβ deposition, tau fibril formation, synapse loss,
neurodegeneration, and cognitive decline. We find increased AD pathology proteins Aβ1-42 and phosphorylated
(p)-tau-181 in human alcohol use disorder (AUD) brain and after chronic binge ethanol during early life in the 3x-
Tg-AD mouse model. Toll-like Receptor (TLR) proinflammatory signaling is thought to precede gross pathology
in AD, and is a prominent feature of AUD. We find AUD in young individuals is associated with AD protein
accumulation, and chronic binge ethanol treatment in 3x-Tg-AD mice causes persistent upregulation of
proinflammatory genes that correlated strongly with levels of neurotoxic Aβ1-42 and p-tau-181 protein. Thus, we
hypothesize ethanol promotes AD neurotoxic protein pathology by enhancing proinflammatory signaling.
Microglia have emerged as mediators of AD pathology, contributing to Aβ plaque formation, tau propagation,
synapse loss and possibly neurodegeneration. Microglial change phenotype (e.g. resting, phagocytic,
proinflammatory, pruning, or neurotoxic) and microglial activation is thought to precede and promote AD
pathology. Human GWAS as well as human and AD mouse single nuclei RNA sequencing (snRNA-seq) have
identified AD microglia as altered, having increased C1q (pro-synaptic pruning) and reduced resting state
markers (e.g. Tmem119). In human AUD brain, we find reduced resting state microglia (reduced Tmem119)
with proinflammatory microglia. Further, we find chronic binge ethanol in vivo persistently increases C1q and
proinflammatory cytokines mirroring AD. Thus, we hypothesize proinflammatory microglial activation by
chronic heavy/binge ethanol promotes AD Aβ and tau pathology, synapse loss and neurodegeneration.
This hypothesis will be tested in human AD post-mortem brain (Aim 1), and the 3x-Tg-AD mouse model (Aim 2)
that features progressive Aβ and tau pathology.
Apoptotic neuronal cell death is a feature of AD pathology thought to contribute to irreversible cognitive decline.
We find binge ethanol increases neurodegeneration in brain regions known to have neuronal loss in AD such as
prefrontal cortex (PFC) and hippocampus. Our studies implicate proinflammatory Toll-like Receptor (TLR)
activation and microglial to neuronal interactions that lead to apoptotic neuronal cell death. We find chronic
binge ethanol increases HMGB1-TLR4 signaling to activate microglia. Proinflammatory microglia secrete the
miRNA let-7b that we found activates TLR7 in neurons. Let-7b-TLR7 signaling in neurons induces apoptotic
neuronal cell death via the TNF-receptor superfamily apoptosis-inducing ligand (TRAIL). TLR4, HMGB1, let-7
and TRAIL have each been implicated in AD pathology. However, a link in AD neurodegeneration has not been
identified. We hypothesize chronic binge ethanol promotes AD neurodegeneration by enhancing TRAIL-
mediated apoptotic neuronal cell death. This hypothesis will be tested in human AD post-mortem brain (Aim
1), and the 5xFAD AD mouse model (Aim 3) that features Aβ-induced apoptotic neuronal death.
摘要
长期大量饮酒或酗酒与痴呆症和阿尔茨海默病(AD)风险增加有关,
尽管与疾病病理有关的机制尚未确定。AD病理学遵循的是
Aβ沉积、tau原纤维形成、突触丢失、
神经退化和认知能力下降。我们发现AD病理蛋白Aβ1-42和磷酸化增加
(P)-tau-181在人类酒精使用障碍(AUD)脑中和慢性酗酒后早期生命中的3倍-tau-181
TG-AD小鼠模型。Toll样受体(TLR)促炎症信号被认为先于大体病理
在AD中,并且是AUD的一个显著特征。我们发现年轻人的AUD与AD蛋白有关
在3x-TG-AD小鼠中积聚和慢性酗酒治疗导致持续上调
促炎基因与神经毒性A tau-1-42和p-β-181蛋白水平密切相关。因此,我们
假设乙醇通过增强促炎信号来促进AD神经毒性蛋白的病理改变。
小胶质细胞是AD病理的中介细胞,参与了Aβ斑块的形成、tau的增殖、
突触丢失,可能还有神经变性。小胶质细胞改变表型(如静息、吞噬、
促炎、修剪或神经毒性)和小胶质细胞激活被认为是AD的先兆和促进因素
病理学。人GWAS以及人和AD小鼠的单核RNA测序(SnRNA-seq)
发现AD小胶质细胞改变,增加了C1q(突触前修剪)和减少了静息状态
标记(例如Tem119)。在人的AUD脑中,我们发现静息状态的小胶质细胞减少(减少的Tem119)
有促炎的小胶质细胞。此外,我们还发现,体内长期酗酒会持续增加C1q和
促炎细胞因子反映AD。因此,我们假设促炎性小胶质细胞激活是通过
长期大量饮酒会促进AD Aβ和tau病理、突触丢失和神经变性。
这一假设将在人类AD死后脑(AIM 1)和3x-TG-AD小鼠模型(AIM 2)中进行验证
这是以进行性Aβ和tau病理为特征的。
神经细胞凋亡是阿尔茨海默病的一个病理特征,被认为是导致不可逆转的认知功能下降的原因之一。
我们发现,酗酒会增加AD中已知神经元丢失的脑区的神经变性,例如
前额叶皮质(PFC)和海马体。我们的研究涉及促炎性Toll样受体(TLR)
激活和小胶质细胞与神经元的相互作用,导致神经细胞的凋亡。我们发现慢性
酗酒会增加HMGB1-TLR4信号,从而激活小胶质细胞。促炎小胶质细胞分泌
我们发现的miRNA let-7b可以激活神经元中的TLR7。神经元中的let-7b-TLR7信号诱导细胞凋亡
肿瘤坏死因子受体超家族凋亡诱导配体(TRAIL)介导的神经细胞死亡。TLR4、HMGB1、LET-7
和TRAIL都与AD的病理有牵连。然而,阿尔茨海默病与神经退行性变之间的联系并不是
确认身份。我们假设长期酗酒通过增强TRAIL促进AD神经退行性变-
介导的神经细胞凋亡。这一假说将在人类AD死后脑(AIM)中得到验证
1),以及5xFAD小鼠模型(Aim 3),该模型以Aβ诱导的神经元凋亡为特征。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
FULTON T CREWS其他文献
FULTON T CREWS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('FULTON T CREWS', 18)}}的其他基金
2/2 Partnerships to Enhance Alcohol Research Across NCCU and UNC (PEAR-NC)
2/2 加强 NCCU 和 UNC 酒精研究的合作伙伴关系 (PEAR-NC)
- 批准号:
10705685 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
2/2 Partnerships to Enhance Alcohol Research Across NCCU and UNC (PEAR-NC)
2/2 加强 NCCU 和 UNC 酒精研究的合作伙伴关系 (PEAR-NC)
- 批准号:
10541708 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
Microglia Activation and TLR-induced Neurodegeneration by Alcohol Promotes Progression of Alzheimer Pathology
酒精引起的小胶质细胞激活和 TLR 诱导的神经变性促进阿尔茨海默病病理学的进展
- 批准号:
10625518 - 财政年份:2020
- 资助金额:
$ 38.88万 - 项目类别:
Microglia Activation and TLR-induced Neurodegeneration by Alcohol Promotes Progression of Alzheimer Pathology
酒精引起的小胶质细胞激活和 TLR 诱导的神经变性促进阿尔茨海默病病理学的进展
- 批准号:
10410531 - 财政年份:2020
- 资助金额:
$ 38.88万 - 项目类别:
MR HISTOLOGY OF THE ADULT RAT, COMPARING IN VIVO AND EX VIVO IMAGES
成年大鼠的 MR 组织学,体内和离体图像的比较
- 批准号:
8363199 - 财政年份:2011
- 资助金额:
$ 38.88万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
PROTEMO: Emotional Dynamics Of Protective Policies In An Age Of Insecurity
PROTEMO:不安全时代保护政策的情绪动态
- 批准号:
10108433 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
EU-Funded
The role of dietary and blood proteins in the prevention and development of major age-related diseases
膳食和血液蛋白在预防和发展主要与年龄相关的疾病中的作用
- 批准号:
MR/X032809/1 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Fellowship
Atomic Anxiety in the New Nuclear Age: How Can Arms Control and Disarmament Reduce the Risk of Nuclear War?
新核时代的原子焦虑:军控与裁军如何降低核战争风险?
- 批准号:
MR/X034690/1 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Fellowship
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341426 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Continuing Grant
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341424 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Continuing Grant
Doctoral Dissertation Research: Effects of age of acquisition in emerging sign languages
博士论文研究:新兴手语习得年龄的影响
- 批准号:
2335955 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Standard Grant
The economics of (mis)information in the age of social media
社交媒体时代(错误)信息的经济学
- 批准号:
DP240103257 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Discovery Projects
How age & sex impact the transcriptional control of mammalian muscle growth
你多大
- 批准号:
DP240100408 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Discovery Projects
Supporting teachers and teaching in the age of Artificial Intelligence
支持人工智能时代的教师和教学
- 批准号:
DP240100111 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Discovery Projects
Enhancing Wahkohtowin (Kinship beyond the immediate family) Community-based models of care to reach and support Indigenous and racialized women of reproductive age and pregnant women in Canada for the prevention of congenital syphilis
加强 Wahkohtowin(直系亲属以外的亲属关系)以社区为基础的护理模式,以接触和支持加拿大的土著和种族育龄妇女以及孕妇,预防先天梅毒
- 批准号:
502786 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Directed Grant