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)是痴呆症的主要原因,其特征是记忆丧失和
项目成果
期刊论文数量(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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