MHCI and synapse loss in Alzheimer's disease models

总结 尽管几十年的研究，阿尔茨海默病（AD）的原因仍然不完全了解，目前 治疗仅提供最小的症状缓解，并且没有已知的治愈方法。AD一直是 与突触和免疫信号通路的畸变有关。然而，一个关键的差距， 知识是缺乏对这两种途径如何交叉沟通以启动和维持AD洞察力， 相关赤字。我们实验室的工作表明，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传导与AD中的突触缺陷联系起来的有吸引力的候选者。MHCI 分子在大脑中表达，特别是在神经元和突触中，在那里它们限制兴奋性 突触密度和功能。最近，我们发现表面MHCI（sMHCI）在对 β淀粉样蛋白（Aβ）和MHCI的缺失阻止了Aβ诱导的突触缺失，从而暗示了这种免疫信号传导 AD病理学的研究。MHCI可能通过一种新的相互作用引起这种突触变性， 最近在MHCI和神经连接素-1（NL 1）之间发现，NL 1是一种调节 突触形成和可塑性。NL 1被Aβ下调，这种下调对于Aβ诱导的 突触密度降低。NL 1在AD患者中也被证明是失调的。我们一起， 结果提示MHCI通过NL 1作用于AD引起突触丢失，并诱导 依赖于大脑的行为缺陷本提案的中心目标是确定 在AD相关的突触和神经元中，MHCI信号传导及其与突触调节剂NL 1的相互作用 行为表型为了解决这个假设，我们的实验室已经从多年的研究中收集了工具， 与MHCI和NL 1相关，这是一种用于研究突触的创新和新型长期活体成像试验 动态，以及AD研究和行为测定新人员的专业知识。我们建议探索 三个目的：（i）确定sMHCI的变化是否是体外Aβ诱导的突触丢失所必需的，（ii）确定是否 sMHCI需要NL 1信号传导以在体外引起Aβ诱导的突触丧失，和（iii）确定sMHCI是否是 所需的AD相关的体内突触和行为表型。如果成功的话，这一提议将提供 对MHCI作为减轻突触和认知损害的治疗靶点的潜力的有价值的见解 与AD相关的表型

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.