Innate immune signaling at the synapse in development and pathological Alzheimer’s disease
发育和病理性阿尔茨海默病中突触的先天免疫信号传导
基本信息
- 批准号:10343757
- 负责人:
- 金额:$ 40.94万
- 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:2020-03-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAPP-PS1ActinsAdultAffinityAge-MonthsAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmyloid beta-ProteinAnatomyAutopsyBindingBiochemistryBrainCellsCerebral cortexCerebrumClinical TrialsComplementCrystallizationDementiaDepositionDevelopmentDiseaseDrug TargetingElectrophysiology (science)EventFamilyFrontotemporal DementiaGene ExpressionGene FamilyGenesGeneticGenetic TranscriptionGenetic studyGoalsHLA-A geneHealthHistocompatibilityHumanImmuneImmune signalingImmune systemImmunoglobulinsImmunohistochemistryImmunologic ReceptorsIn Situ HybridizationInflammationLeadLearningLeukocytesLigandsLinkMHC Class I GenesMediatingMediator of activation proteinMemoryMemory LossMethodsMolecularMusNerve BlockNervous system structureNeurobiologyNeurofibrillary TanglesNeuronsOrganoidsOutcomePathologicPathologyPathway interactionsPharmacologyProcessProsencephalonProteinsRecombinant ProteinsResearchResolutionRiboTagRoleSamplingSenile PlaquesSignal PathwaySignal TransductionStructureSynapsesSynaptic plasticitySystemTestingTranscriptTransgenic ModelValidationVertebral columnVisual system structureabeta oligomerautosomal dominant Alzheimer&aposs diseasecell typecofilincritical developmental perioddepolymerizationearly onsetexperienceexperimental studyfrontal lobegenome wide association studyhippocampal pyramidal neuronin vivoinduced pluripotent stem cellinterestmouse modelnanomolarneurotransmissionnew therapeutic targetnovelnovel therapeuticspostnatalreceptorrelating to nervous systemsynaptic functionsynaptic pruningtargeted treatmenttau Proteinstau-1transcriptometranscriptome sequencingvision development
项目摘要
Pathological Alzheimer’s disease (AD) is a major cause of dementia characterized by memory loss and
aggregation of insoluble beta amyloid plaques and tau tangles. Memories are stored at synapses, and it is
thought that an early driver of dementia may be synapse pruning occurring even before plaque deposition.
Extensive activity-dependent synaptic pruning also occurs during developmental critical periods when learning
and experience strengthen and stabilize actively used synapses, while others weaken and are pruned. In an
unbiased in vivo screen for genes regulated by neural activity during visual system development, my lab made
the unexpected discovery that specific Major Histocompatibility Class I (MHCI) molecules, famous for their
immune system roles, are expressed in neurons and at synapses. Next, we identified an innate immune MHCI
receptor expressed in neurons: PirB (Paired immunoglobulin-like receptor B). Functional studies in mice reveal
that the MHCI - PirB axis is required for synapse pruning during normal development. Genetic deletion of PirB
selectively in cortical pyramidal neurons, or pharmacologic blockade using a recombinant protein, rapidly
generates new spines and functional synapses even in adult cerebral cortex. In the APP/PS1 transgenic model
of autosomal dominant AD, mice lacking PirB are protected from memory loss at 9 months of age despite high
levels of beta amyloid. Remarkably, PirB is a receptor for soluble beta amyloid oligomers, with high affinity
saturable binding. This interaction hyperactivates cofilin signaling which drives actin depolymerization and
contributes to synapse pruning in the APP/PS1 AD mouse model. In human the LilrB (leukocyte immunoglobulin-
like receptor B) family of 5 related molecules are PirB homologs. Similar to PirB, LilrB1 and LilrB2 are known to
bind MHCI ligands, including HLA-A, B and C alleles, which are implicated in human GWAS and gene expression
studies of AD. We discovered that LilrB2 binds soluble beta amyloid oligomers with nanomolar affinity, and LilrB2
protein is expressed in human frontal lobe. A crystal structure of the interaction between beta amyloid and LilrB2
has been solved, confirming genuine structural interactions and pointing to novel drug targets for AD. A major
goal of this research is to test the hypothesis that innate immune signaling via MHCI-PirB/LilrB at the synapse is
disrupted by pathological oAbeta, and to connect observations in mice to human neurobiology by (1) studying
MHCI-PirB dependent signaling in neurons using RiboTag cell type- specific transcription profiling in AD model
mice, and (2) by identifying and studying the function of human homologs, the HLA Class I and LilrB receptor
families, in 3-dimensional forebrain organoids derived from human iPSCs, followed by validation in brain samples.
Results from these studies will build a bridge between mouse models of AD and human neurons. They should
also provide mechanistic information about how nervous and immune systems communicate at the synapse and
open up new therapeutic avenues for treating synapse pruning disorders in development and in Alzheimer’s
disease.
病理性阿尔茨海默病(AD)是痴呆的主要原因,其特征在于记忆丧失,
不溶性β淀粉样蛋白斑和tau缠结的聚集。记忆储存在突触中,
认为痴呆症的早期驱动因素可能是甚至在斑块沉积之前发生的突触修剪。
广泛的活动依赖性突触修剪也发生在发育的关键时期,
经验强化和稳定活跃使用的突触,而其他的则减弱和被修剪。中
在视觉系统发育过程中,我的实验室进行了一项无偏见的体内筛选,以寻找受神经活动调节的基因。
这一意外发现表明,特定的主要组织相容性I类(MHCI)分子,以其
免疫系统的作用,在神经元和突触中表达。接下来,我们发现了一种先天免疫MHCI
在神经元中表达的受体:PirB(配对免疫球蛋白样受体B)。小鼠功能研究显示
MHCI-PirB轴是正常发育过程中突触修剪所必需的。PirB基因缺失
选择性地在皮质锥体神经元中,或使用重组蛋白的药理学阻断,
甚至在成人大脑皮质中也会产生新的棘和功能性突触。在APP/PS1转基因模型中,
在常染色体显性AD中,缺乏PirB的小鼠在9个月大时免受记忆丧失,尽管高的PirB水平。
β淀粉样蛋白水平值得注意的是,PirB是可溶性β淀粉样蛋白寡聚体的受体,具有高亲和力,
可饱和结合这种相互作用过度激活了cofilin信号传导,其驱动肌动蛋白解聚,
有助于APP/PS1 AD小鼠模型中的突触修剪。在人类中,LilrB(白细胞免疫球蛋白-
类受体B)家族的5个相关分子是Pir B同系物。与PirB类似,已知LilrB 1和LilrB 2
结合MHCI配体,包括HLA-A、B和C等位基因,其与人GWAS和基因表达有关
AD的研究。我们发现LilrB 2以纳摩尔亲和力结合可溶性β淀粉样蛋白寡聚体,
在人类额叶中表达。β淀粉样蛋白与LilrB 2相互作用的晶体结构
已经解决,确认真正的结构相互作用,并指出新的药物靶点的AD。一个主要
本研究的目的是检验突触处通过MHCI-PirB/LilrB的先天免疫信号传导是
被病理性oAbeta破坏,并通过(1)研究将小鼠的观察结果与人类神经生物学联系起来
在AD模型中使用RiboTag细胞类型特异性转录谱分析的神经元中的MHCI-PirB依赖性信号传导
小鼠,和(2)通过鉴定和研究人类同源物的功能,HLA I类和LilrB受体
在来源于人iPSC的3维前脑类器官中,随后在脑样品中进行验证。
这些研究的结果将在AD小鼠模型和人类神经元之间建立桥梁。他们应该
还提供了神经和免疫系统如何在突触处交流的机制信息,
为治疗发育中的突触修剪障碍和阿尔茨海默氏症开辟了新的治疗途径,
疾病
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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Carla J Shatz其他文献
Subplate Neurons Undergo Cell Death Following Hypoxic Ischemic Brain Injury
- DOI:
10.1203/00006450-199904020-00260 - 发表时间:
1999-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Patrick S McQuillen;Carla J Shatz;Donna M Ferriero - 通讯作者:
Donna M Ferriero
Brain Waves and Brain Wiring: The Role of Endogenous and Sensory-Driven Neural Activity in Development
脑电波与大脑布线:内源性和感觉驱动的神经活动在发育中的作用
- DOI:
10.1203/00006450-199904010-00001 - 发表时间:
1999-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Anna A Penn;Carla J Shatz - 通讯作者:
Carla J Shatz
Carla J Shatz的其他文献
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{{ truncateString('Carla J Shatz', 18)}}的其他基金
Determining cell-type specificity for a nonclassical MHC class I during an activity-dependent cortical critical period.
确定活动依赖性皮质关键期非经典 MHC I 类的细胞类型特异性。
- 批准号:
10705621 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
Determining cell-type specificity for a nonclassical MHC class I during an activity-dependent cortical critical period.
确定活动依赖性皮质关键期非经典 MHC I 类的细胞类型特异性。
- 批准号:
10426738 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
Innate immune signaling at the synapse in development and pathological Alzheimer’s disease
发育和病理性阿尔茨海默病中突触的先天免疫信号传导
- 批准号:
10115567 - 财政年份:2020
- 资助金额:
$ 40.94万 - 项目类别:
Innate immune signaling at the synapse in development and pathological Alzheimer’s disease
发育和病理性阿尔茨海默病中突触的先天免疫信号传导
- 批准号:
10582575 - 财政年份:2020
- 资助金额:
$ 40.94万 - 项目类别:
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