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：
10115567
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/10115567
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 Cerebrum Clinical Trials Complement Crystallization 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 Human Immune Immune signaling Immune system Immunoglobulins Immunohistochemistry Immunologic Receptors In Situ Hybridization Inflammation Lead Learning Leukocytes Ligands Link MHC Class I Genes Mediating Mediator of activation protein Memory Memory Loss Methods Molecular Mus Nerve Block Nervous system structure Neurobiology Neurofibrillary Tangles Neurons Organoids Outcome Pathologic Pathology Pathway interactions Pharmacology 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 structure 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 hippocampal pyramidal neuron in vivo induced pluripotent stem cell interest mouse model nanomolar neurotransmission new therapeutic target novel novel therapeutics postnatal receptor relating to nervous system 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) 是导致痴呆症的主要原因，其特征是记忆丧失和不溶性β淀粉样斑块和tau蛋白缠结的聚集存储在突触中。认为痴呆的早期驱动因素可能是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会发生在学习的发育关键时期经验会增强和稳定积极使用的突触，而其他突触则会减弱并被修剪。我的实验室对视觉系统发育过程中受神经活动调节的基因进行无偏见的体内筛选意外的发现，特定的主要组织相容性 I 类 (MHCI) 分子，以其接下来，我们确定了先天免疫 MHCI。神经元中表达的受体：PirB（配对免疫球蛋白样受体 B）的功能研究表明。 MHCI - PirB 轴是正常发育过程中突触修剪所必需的。选择性地作用于皮质锥体神经元，或使用重组蛋白进行药物阻断，快速在 APP/PS1 转基因模型中，甚至在成人大脑皮层中也会产生新的棘和功能性突触。在常染色体显性 AD 中，缺乏 PirB 的小鼠在 9 个月大时可以免受记忆丧失，尽管其记忆力很高值得注意的是，PirB 是可溶性 β 淀粉样蛋白寡聚物的受体，具有高亲和力。这种相互作用过度激活丝动蛋白信号传导，从而驱动肌动蛋白解聚和 LilrB（白细胞免疫球蛋白）有助于 APP/PS1 AD 小鼠模型中的突触修剪。类似受体 B) 家族的 5 个相关分子是 PirB 同源物，已知 LilrB1 和 LilrB2 与 PirB 类似。结合 MHCI 配体，包括 HLA-A、B 和 C 等位基因，这些基因与人类 GWAS 和基因表达有关我们发现 LilrB2 以纳摩尔亲和力结合可溶性 β 淀粉样蛋白寡聚体，并且 LilrB2 蛋白质在人类额叶中表达，β淀粉样蛋白和LilrB2之间相互作用的晶体结构。已解决，证实了真正的结构相互作用并指出了 AD A 主要的新药物靶点。本研究的目的是检验突触处通过 MHCI-PirB/LilrB 进行的先天免疫信号传导的假设被病理性 oAbeta 破坏，并通过 (1) 研究将小鼠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神经元中的 MHCI-PirB 依赖性信号传导小鼠，以及 (2) 通过识别和研究人类同系物、HLA I 类和 LilrB 受体的功能家族，在源自人类 iPSC 的 3 维前脑类器官中进行研究，然后在大脑样本中进行验证。这些研究的结果将在 AD 小鼠模型和人类神经元之间架起一座桥梁。还提供有关神经和免疫系统如何在突触处沟通的机制信息为治疗发育过程中的突触修剪障碍和阿尔茨海默病开辟新的治疗途径疾病。