MHCI and synapse loss in Alzheimer's disease models

阿尔茨海默病模型中的 MHCI 和突触损失

• 批准号: 10372774
• 负责人: A Kimberley McAllister
• 金额: $ 42.4万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372774
• 关键词: APP-PS1; Address; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Animal Model; Area; Behavioral; Behavioral Assay; Biological Assay; Brain; Cell Adhesion Molecules; Cognitive; Cognitive deficits; Data; Dendritic Spines; Disease; Emotional; Excision; Excitatory Synapse; Exhibits; Exploratory/Developmental Grant; Family; Future; Glutamates; Goals; Hippocampus (Brain); Human; Human Resources; Image; Imaging Techniques; Immune; Immune signaling; Impaired cognition; In Vitro; Individual; Intervention; Knockout Mice; Knowledge; Learning; Link; Location; Major Histocompatibility Complex; Measures; Mediating; Memory; Memory impairment; Molecular; Molecular Target; Mus; Neuraxis; Neurons; Pathology; Pathway interactions; Peptides; Peripheral; Pharmacology; Phenotype; Proteins; Research; Rewards; Role; Senile Plaques; Signal Pathway; Signal Transduction; Surface; Synapses; Testing; Therapeutic; Therapeutic Intervention; Time; Work; behavioral phenotyping; beta-2 Microglobulin; density; human model; in vivo; innovation; insight; nervous system disorder; neuroligin 1; new therapeutic target; novel; prevent; reduce symptoms; response; synaptogenesis; therapeutic target; tool

SUMMARY Despite decades of research, the cause of Alzheimer’s disease (AD) remains incompletely understood, current treatments provide only minimal symptom relief, and there are no known cures. AD has consistently been associated with aberrations in both synaptic and immune signaling pathways. However, a key gap in knowledge is a lack of insight into how these two pathways cross communicate to initiate and sustain AD- associated deficits. Work from our lab indicates that the classical major histocompatibility complex I (MHCI) immune molecules are attractive candidates for linking immune signaling to synaptic deficits in AD. MHCI molecules are expressed in the brain, specifically in neurons and at synapses, where they limit excitatory synapse density and function. Recently, we found that surface MHCI (sMHCI) is upregulated in response to amyloid-β (Aβ) and loss of MHCI prevents Aβ-induced synapse loss, thereby implicating this immune signaling in AD pathology for the first time. MHCI may cause this synaptic degeneration through a novel interaction we recently discovered between MHCI and neuroligin-1 (NL1), a synaptic adhesion molecule that modulates synapse formation and plasticity. NL1 is downregulated by Aβ and this decrease is necessary for Aβ-induced decreases in synapse density. NL1 has also been shown to be misregulated in humans with AD. Together, our results suggest the hypothesis that MHCI acts through NL1 to cause synapse loss in AD and induce hippocampal-dependent behavioral deficits. The central goal of this proposal is to determine the role for MHCI signaling, and its interaction with the synaptic modulator NL1, in AD-associated synaptic and behavioral phenotypes. To address this hypothesis, our lab has assembled tools from years of research related to both MHCI and NL1, an innovative and novel long-term live imaging assay to study synapse dynamics, and the expertise of new personnel in AD research and behavioral assays. We propose to explore three aims: (i) determine if changes in sMHCI are required for Aβ-induced synapse loss in vitro, (ii) determine if sMHCI requires NL1 signaling to cause Aβ-induced synapse loss in vitro, and (iii) determine if sMHCI is required for AD-associated in vivo synaptic and behavioral phenotypes. If successful, this proposal will provide valuable insight into the potential of MHCI as a therapeutic target for mitigating the synaptic and cognitive phenotypes associated with AD.

摘要 尽管经过了几十年的研究，阿尔茨海默病(AD)的病因仍然不完全清楚，目前 治疗只能起到最小的缓解症状的作用，而且目前还没有已知的治疗方法。广告一直以来都是 与突触和免疫信号通路的异常有关。然而，一个关键的差距是 缺乏对这两条途径如何交叉沟通以启动和维持AD的洞察力- 相关的赤字。我们实验室的研究表明，经典的主要组织相容性复合体I(MHCI) 免疫分子是将免疫信号与AD的突触缺陷联系起来的有吸引力的候选分子。MHCI 分子在大脑中表达，特别是在神经元和突触中，它们限制了兴奋性。 突触密度和功能。最近，我们发现表面MHCI(SMHCI)上调是对 淀粉样蛋白-β(A-β)和MHCI的丢失可阻止β诱导的突触丢失，从而参与这一免疫信号 在AD病理学中首次出现。MHCI可能通过一种新的相互作用引起这种突触退化 最近在MHCI和神经连接蛋白-1(NL1)之间发现的，神经连接蛋白-1是一种突触黏附分子，调节 突触的形成和可塑性。NL1被β下调，这种下调对于β诱导的AFP是必要的 突触密度降低。在阿尔茨海默病患者中，NL1基因也被证明是错误调控的。在一起，我们的 结果提示，MHCI通过NL1导致AD突触丢失并诱导 海马区依赖的行为缺陷。该提案的中心目标是确定 MHCI信号及其与突触调节剂NL1的相互作用在AD相关突触和 行为表型。为了解决这一假设，我们的实验室从多年的研究中收集了一些工具 与MHCI和NL1相关，一种研究突触的创新和新颖的长期活体成像方法 动力学，以及AD研究和行为分析方面的新人员的专业知识。我们建议探索 三个目标：(I)确定β诱导的体外突触丢失是否需要sMHCI的变化；(Ii)确定是否 SMHCI需要NL1信号来导致β诱导的体外突触丢失，以及(Iii)确定sMHCI是否 AD相关的体内突触和行为表型所必需的。如果成功，这项提议将提供 MHCI作为缓解突触和认知障碍的治疗靶点的潜力的有价值的见解 与AD相关的表型。