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: 10343757
• 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
• 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/10343757
• 关键词: 3-Dimensional; APP-PS1; Actins; Adult; Affinity; Age-Months; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' 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' 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

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