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：
10582575
负责人：
Carla J Shatz
金额：
$ 40.94万
依托单位：
STANFORD UNIVERSITY
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：
https://reporter.nih.gov/project-details/10582575
关键词：
3-Dimensional APP-PS1 Actins Adult Affinity Age Months Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Anatomy Autopsy Binding Biochemistry Brain Cells Cerebral cortex Clinical Trials Communication Complement Dementia Deposition Development Disease Drug Targeting Electrophysiology (science)Event Family Frontotemporal Dementia Gene Expression Gene Family Genes Genetic Genetic Transcription Genetic study Goals HLA-A gene Health Histocompatibility Homologous Gene Human Immune Immune signaling Immune system Immunoglobulins Immunohistochemistry Immunologic Receptors In Situ Hybridization Inflammation Learning Leukocytes Ligands Link MHC Class I Genes Mediating Mediator Memory Memory Loss Methods Molecular Mus Nerve Block Nervous System Neurobiology Neurofibrillary Tangles Neurons Organoids Outcome Pathologic Pathology Pathway interactions Process Prosencephalon Proteins Recombinant Proteins Research Resolution RiboTag Role Sampling Senile Plaques Signal Pathway Signal Transduction Structure Synapses Synaptic plasticity System Testing Transcript Transgenic Model Validation Vertebral column Visual System abeta oligomer autosomal dominant Alzheimer&apos s disease cell type cofilin critical developmental period depolymerization early onset experience experimental study frontal lobe genome wide association study glial activation hippocampal pyramidal neuron in vivo induced pluripotent stem cell interest mouse model nanomolar neural neurotransmission new therapeutic target novel novel therapeutics pharmacologic postnatal protein aggregation receptor synaptic function synaptic pruning targeted treatment tau Proteins tau-1 transcriptome transcriptome sequencing vision 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.

病理性阿尔茨海默氏病（AD）是痴呆症的主要原因，其特征是记忆力丧失和不溶性β淀粉样蛋白斑块和tau缠结的聚集。记忆存储在突触中，它是认为甚至在牙菌斑沉积之前就会发生痴呆症的早期驱动力。在学习期间，在发展的关键时期还会发生广泛的活动依赖性突触修剪并经验增强和稳定积极使用的突触，而其他人则弱且修剪。我的实验室制造意外的发现，特定的主要组织相容性I类（MHCI）分子以其免疫系统作用，在神经元和突触中表达。接下来，我们确定了先天免疫MHCI 在神经元中表达的受体：PIRB（成对的免疫球蛋白样受体B）。小鼠的功能研究表明在正常发育过程中，MHCI -PIRB轴是突触修剪所必需的。 PIRB的遗传缺失在皮质金字塔神经元中有选择地使用重组蛋白的药理学阻断，迅速即使在成年大脑皮层中，也会产生新的刺和功能突触。在应用程序/PS1转基因模型中常染色体显性广告中，缺乏PIRB的小鼠受到保护在9个月时代高的记忆损失。 β淀粉样蛋白的水平。值得注意的是，PIRB是固体β淀粉样蛋白低聚物的受体，具有高亲和力可饱和结合。这种相互作用过度激活Cofilin信号传导，驱动肌动蛋白沉积和在APP/PS1 AD鼠标模型中促进突触修剪。在人类中（白细胞免疫球蛋白 - 像接收器b）5个相关分子家族是PIRB同源物。与PIRB相似，Lilrb1和Lilrb2已知结合MHCI配体，包括HLA-A，B和C等位基因，在人GWA和基因表达中实现 AD研究。我们发现lilrb2结合具有纳摩尔亲和力的固体β淀粉样蛋白低聚物和lilrb2 蛋白质在人额叶中表达。 β-淀粉样蛋白和lilrb2之间相互作用的晶体结构已经解决了，证实了真正的结构相互作用，并指出了AD的新药物靶标。专业这项研究的目标是检验以下假设：突触中通过MHCI-PIRB/LILRB的先天免疫信号是受病理性的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 MHCI-PIRB使用AD模型中的Ribotag细胞类型转录分析在神经元中的依赖性信号传导小鼠，（2）通过识别和研究人类同源物的功能，HLA I类和LILRB接收器家族中的三维前脑器官，源自人IPSC，随后在脑样本中进行验证。这些研究的结果将在AD和人类神经元的小鼠模型之间建立桥梁。他们应该还提供有关在突触中如何进行神经和免疫系统沟通的机械信息打开新的治疗途径，用于治疗发展中的突触修剪障碍和阿尔茨海默氏症疾病。