Disruption of neuronal signaling in Alzheimer’s disease and rescue by manipulating the innate immune receptor PirB

阿尔茨海默病神经元信号传导的破坏以及通过操纵先天免疫受体 PirB 进行挽救

基本信息

批准号：
10231468
负责人：
Johanna Elizabeth Tomorsky
金额：
$ 6.64万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231468
关键词：
APP-PS1 Acute Adult Affinity Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid beta-Protein Astrocytes Automobile Driving Behavioral Behavioral Paradigm Binding Biochemical Cells Cessation of life Crystallization Development Disease Progression Dominant-Negative Mutation Electrophysiology (science)Electroporation Functional disorder Gene Expression Gene Proteins Genes Goals Histocompatibility Homologous Gene Human Immune Immune signaling Immunoglobulins Immunologic Receptors Impaired cognition Inflammation Injury Knock-out Lead Length Ligands Link LoxP-flanked allele Mass Spectrum Analysis Measures Memory Memory Loss Memory impairment Microglia Mus Neurofibrillary Tangles Neurons Pathologic Pathway interactions Pattern Phosphorylation Population Prosencephalon Protein Dephosphorylation Proteins Recombinant Proteins Reporting Research RiboTag Role Signal Pathway Signal Transduction Structure Synapses Synaptic plasticity Synaptosomes Tamoxifen Techniques Testing Therapeutic Time Transgenes abeta accumulation aged autosomal dominant Alzheimer&apos s disease calmodulin-dependent protein kinase II cell type cofilin conditional knockout critical period druggable target excitatory neuron experimental study follow-up hyperphosphorylated tau immune activation in utero knock-down macrophage mouse model nanomolar neuroinflammation neuron loss neurotransmission new growth novel oAβ prevent rapid growth receptor response small hairpin RNA synaptic function synaptic pruning therapeutic target transcriptome sequencing transcriptomics

项目摘要

Project Summary Alzheimer’s disease (AD) is becoming more prevalent as our population ages and is characterized by devastating memory loss and cognitive impairment. The pruning of neuronal synapses contributes to the pathology of AD and is the best correlate of cognitive decline. Both oligomeric amyloid beta and neuroinflammatory mechanisms can lead to synapse pruning in AD. While neurons and immune cells have been shown to interact to drive pruning, the neuronal signaling downstream of this interaction is not well understood. A major goal of this proposal is to determine neuronal signaling mechanisms driving synapse pruning in mouse models of autosomal dominant AD at two ages and under varying conditions of both aggregated amyloid beta and immune activation. Synapse pruning occurs naturally throughout development, and one hypothesis is that developmental pruning mechanisms are dysregulated in AD. The Shatz lab made the surprising discovery that the innate immune receptor, PirB, is expressed in neurons and has roles in synapse pruning over development. In addition, PirB knockout in adult mice, either globally or in excitatory neurons alone, facilitates the rapid growth of new synapses and re-opens critical period-like synaptic plasticity. PirB and its human homologue, LilrB2, have both been shown to bind amyloid beta at high affinities, and germline global PirB knockout was shown to protect against memory loss in the APP/PS1 mouse model of AD. While global germline knockout was protective, in a therapeutic context, it is also important to determine the effect of PirB blockade in normally reared adult mice at various stages of disease progression. In addition, while the Shatz lab identified a signaling pathway linking PirB to synapse pruning, via the dephosphorylation of cofilin, no other signaling pathways have been examined downstream of PirB in APP/PS1 mice. Here, I propose to test the hypothesis that neuronal gene expression is dysregulated in AD model mice and can be restored with PirB KO, protecting against synapse loss. The experiments proposed should identify new signaling pathways in neurons and at synapses downstream of PirB in AD model mice. I also propose to block PirB in normally reared adult APP/PS1 mice to determine the therapeutic potential of PirB/LilrB2 blockade in AD. I focus on two stages of disease progression: 1) early, before plaque formation but when synaptic and memory deficits have been reported, and 2) late, after plaque formation and heightened immune activation. The central goal of this proposal is to use transcriptomic, biochemical, electrophysiological, and behavioral techniques to elucidate signaling pathways downstream of PirB/LilrB2 in AD and demonstrate the therapeutic potential of PirB blockade to ‘treat’ memory loss in APP/PS1 model mice. The long-term aim of this research is to contribute to our understanding of the signaling mechanisms leading to synaptic pruning in Alzheimer’s disease, as a first step toward finding potential therapies and therapeutic targets.

项目概要随着人口老龄化，阿尔茨海默病 (AD) 变得越来越普遍，其特点是神经突触的修剪会导致毁灭性的记忆丧失和认知障碍。 AD 的病理学是认知能力下降的最佳相关性。神经炎症机制可以导致 AD 中的突触修剪，而神经元和免疫细胞则可以。已被证明可以相互作用来驱动修剪，但这种相互作用下游的神经信号传导并不好该提案的一个主要目标是确定驱动突触的神经信号机制。在两个年龄和不同条件下对常染色体显性 AD 小鼠模型进行修剪聚集的β淀粉样蛋白和免疫激活。突触修剪在整个发育过程中自然发生，一种假设是发育过程 Shatz 实验室的惊人发现是，AD 中的修剪机制失调。免疫受体 PirB 在神经元中表达，在发育过程中的突触修剪中发挥作用。此外，成年小鼠中的 PirB 敲除，无论是整体敲除还是仅敲除兴奋性神经元，都促进了快速生长新突触并重新开启关键时期的突触可塑性。两者均已被证明能够以高亲和力结合β淀粉样蛋白，并且种系全局 PirB 敲除被证明可以在 AD 的 APP/PS1 小鼠模型中防止记忆丧失。保护性，在治疗背景下，确定 PirB 阻断在正常情况下的效果也很重要此外，沙茨实验室还发现了一种处于疾病进展不同阶段的成年小鼠。连接 PirB 和突触修剪的信号通路，通过丝切蛋白的去磷酸化，没有其他信号传导已在 APP/PS1 小鼠中检查了 PirB 下游的通路。在这里，我建议检验 AD 模型小鼠神经基因表达失调的假设并且可以用 PirB KO 来恢复，防止突触丢失。建议的实验应该确定。我还建议在 AD 模型小鼠的神经元和 PirB 下游突触中发现新的信号通路。在正常饲养的成年 APP/PS1 小鼠中阻断 PirB，以确定 PirB/LilrB2 的治疗潜力我重点关注疾病进展的两个阶段：1）早期，即斑块形成之前，但何时？据报道，突触和记忆缺陷，以及 2) 晚期，在斑块形成和健康的免疫系统之后该提案的中心目标是利用转录组学、生物化学、电生理学和行为技术阐明 AD 中 PirB/LilrB2 的信号下游通路并证明 PirB 阻断“治疗”APP/PS1 模型小鼠记忆丧失的治疗潜力该研究的长期目标。研究旨在帮助我们理解导致突触修剪的信号机制阿尔茨海默病，这是寻找潜在疗法和治疗靶点的第一步。