Innate immune signaling at the synapse in development and pathological Alzheimer’s disease

病理性阿尔茨海默病(AD)是导致痴呆的主要原因，其特征是记忆力丧失和 不溶性β淀粉样斑块和tau缠结的聚集。记忆存储在突触中，它确实是 认为痴呆的早期驱动因素可能是突触修剪，甚至在斑块沉积之前就发生了。 广泛的依赖活动的突触修剪也发生在学习的发育关键期 经验加强和稳定活跃使用的突触，而其他突触则减弱和修剪。在一个 我的实验室在体内无偏见地筛选视觉系统发育过程中受神经活动调控的基因 出人意料的发现，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，我们鉴定了一种先天免疫MHCI 神经元表达的受体：PirB(配对免疫球蛋白样受体B)。对小鼠的功能研究揭示 在正常发育过程中，突触修剪需要MHCI-PirB轴。PirB基因缺失 选择性的皮质锥体神经元，或使用重组蛋白的药物阻断，快速 即使在成人大脑皮层中也会产生新的脊椎和功能性突触。在APP/PS1转基因模型中 在常染色体显性阿尔茨海默病中，缺乏PirB的小鼠在9个月大时免受记忆丧失的影响，尽管高 β淀粉样蛋白水平。值得注意的是，PirB是可溶性β淀粉样寡聚体的受体，具有高亲和力 可饱和装订。这种相互作用过度激活了cofilin信号，从而驱动肌动蛋白解聚和 有助于APP/PS1 AD小鼠模型中突触的修剪。在人类中，LilrB(白细胞免疫球蛋白- 与受体B类似)家族的5个相关分子是PirB同源物。与PirB类似，LilrB1和LilrB2已知 结合MHCI配体，包括与人类GWA和基因表达有关的HLA-A、B和C等位基因 AD的研究。我们发现LilrB2与具有纳摩尔亲和力的可溶性β-淀粉样蛋白低聚物结合，而LilrB2 蛋白质在人类额叶中表达。β-淀粉样蛋白与LilrB2相互作用的晶体结构 已经得到解决，证实了真正的结构相互作用，并指出了AD的新药物靶点。一位少校 这项研究的目的是验证这样的假设，即通过突触处的MHCI-PirB/LilrB的天然免疫信号是 被病理性的oAbeta干扰，并通过(1)研究将小鼠的观察与人类神经生物学联系起来 用核糖核酸标记细胞类型特异性转录图谱研究AD模型中神经元中MHCI-PirB依赖的信号 (2)通过鉴定和研究人类同源物、HLAI类和LilrB受体的功能 从人类IPSCs中提取的三维前脑有机体，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。他们应该 还提供了有关神经和免疫系统如何在突触和 为治疗发育期和阿尔茨海默病中的突触修剪障碍开辟新的治疗途径 疾病。

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.