CaMKII nitrosylation in the age-related decline of synaptic plasticity

CaMKII 亚硝基化在与年龄相关的突触可塑性下降中的作用

• 批准号: 10444721
• 负责人: K. Ulrich Bayer
• 金额: $ 23.67万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444721
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Binding; Brain; Cerebrospinal Fluid; Chromosome 21; Cognition; Dependence; Development; Dose; Down Syndrome; Early Onset Alzheimer Disease; Excitatory Synapse; Follow-Up Studies; Functional disorder; Gene Proteins; Hippocampus (Brain); Impairment; Knock-out; Lead; Learning; Link; Long-Term Potentiation; Mediating; Memory; Movement; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Onset of illness; Pathologic; Patients; Plasma; Protein Precursors; Proteins; Role; Signal Transduction; Synapses; Synaptic plasticity; age related; calmodulin-dependent protein kinase II; insight; mouse model; novel therapeutic intervention; prevent

Project Summary/Abstract Many patients with Down Syndrome (DS) develop early onset Alzheimer’s disease (AD), and an obvious mechanistic link between the two conditions is provided by the β-amyloid (Aβ) precursor protein (APP): Aβ is a major pathological agent in AD, and patients with DS have an extra copy of the APP gene (as it is localized on the chromosome 21 that is triplicated in DS) as well as elevated Aβ levels in plasma and cerebrospinal fluid. Aβ is well known to inhibit hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underly higher brain functions such as learning, memory, and cognition (which are impaired in both AD and DS, albeit in different ways). Indeed, LTP is impaired in mouse models of both AD and DS. LTP is critically mediated by the Ca2+/calmodulin-dependent protein kinase II (CaMKII), and we have recently shown that Aβ interferes with LTP by affecting CaMKII signaling: Normal LTP requires CaMKII movement to excitatory synapses via regulated binding to the NMDA-receptor, and Aβ suppresses this CaMKII movement. Notably, in the AD-related impairment of LTP, APP acts not only as an upstream precursor but also as a downstream effector of Aβ. While the role of APP as Aβ precursor is well established, its role as Aβ effector is just emerging (and has not been examined at all in context of DS). Additionally, while the APP triplication in DS has been suggested as cause for the DS-associated early onset AD, a role in the DS-associated impairment of LTP prior to AD onset remains to be investigated. Here, we will determine the function of APP as Aβ precursor versus effector in a DS mouse model. As APP knockout prevents the Aβ-induced impairments of CaMKII movement and LTP, we hypothesize that the APP gene triplication in Down Syndrome sensitizes to the effects of Aβ on CaMKII movement and LTP (even before the manifestation of early onset AD). We will here determine if hippocampal neurons from a mouse model of DS are more sensitive to the Aβ-induced impairments of CaMKII movement, as reflected by a lower threshold for either dose or duration of Aβ exposure. Follow-up studies will investigate (i) a similar sensitization for Aβ-induced LTP impairments, and (ii) dependence of these effects on the additional copy of APP (by eliminating one of the APP copies in the DS mouse line).

项目摘要/摘要 许多唐氏综合征(DS)患者发展为早发性阿尔茨海默病(AD)，并且明显 这两种情况之间的机制联系是由β-淀粉样蛋白(Aβ)前体蛋白(APP)提供的：β是 AD的主要病原体，DS患者有一个额外的APP基因拷贝(因为它是定位的 在21号染色体上，这是DS的三倍)，以及血浆和脑脊液中Aβ水平的升高。 众所周知，β可以抑制海马长时程增强，这是一种突触可塑性的形式，被认为是 较高的大脑功能，如学习、记忆和认知(在阿尔茨海默病和老年痴呆症中都会受损 DS，尽管方式不同)。事实上，LTP在AD和DS的小鼠模型中都受到了损害。LTP是至关重要的 由钙/钙调蛋白依赖的蛋白激酶II(CaMKII)介导，我们最近发现Aβ 通过影响CaMKII信号干扰LTP：正常LTP需要CaMKII运动才能兴奋 通过调节与NMDA受体的结合而突触，而Aβ抑制这种CaMKII运动。值得注意的是，在 阿尔茨海默病相关的LTP，APP损伤不仅是上游的先兆，也是下游的先兆 β的效应器。虽然APP作为β前体的角色已经确立，但它作为β效应器的角色才刚刚出现 (并且根本没有在DS的上下文中进行检查)。此外，虽然DS中的应用程序三倍于 被认为是DS相关的早发性AD的原因，在DS相关的LTP之前的损害中起作用 至阿尔茨海默病发病尚待调查。在这里，我们将确定APP作为β前体的功能与 DS鼠标模型中的效应器。由于APP基因敲除可阻止Aβ诱导的CaMKII运动损伤 和LTP，我们假设唐氏综合征中的APP基因三倍体对 对CaMKII运动和长时程增强的β(甚至在早发性AD表现之前)。我们将在这里确定 DS小鼠模型的海马神经元对Aβ诱导的CaMKII损伤更敏感 运动，反映在Aβ暴露剂量或持续时间的较低阈值上。后续研究将 研究(I)A-β诱导的长时程增强损伤的类似敏化作用，以及(Ii)这些影响对 应用程序的额外副本(通过删除DS鼠标行中的一个应用程序副本)。