CaMKII nitrosylation in the age-related decline of synaptic plasticity

项目总结/摘要 许多患有唐氏综合征（DS）的患者发展为早发性阿尔茨海默病（AD），并且明显的阿尔茨海默病（AD）是一种慢性疾病。 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：Aβ是 AD中的主要病理因子，并且DS患者具有APP基因的额外拷贝（因为其是局部的 在DS中为三倍的21号染色体上）以及血浆和脑脊液中Aβ水平升高。 众所周知，Aβ抑制海马长时程增强（LTP），这是一种突触可塑性形式， 在更高的大脑功能，如学习，记忆和认知（这是在AD和 （虽然方式不同）。事实上，LTP在AD和DS的小鼠模型中都受损。LTP是关键 由Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）介导，我们最近发现Aβ 通过影响CaMKII信号传导干扰LTP：正常LTP需要CaMKII运动到兴奋性 通过与NMDA受体的调节性结合来调节突触，并且Aβ抑制这种CaMKII运动。特别是在 AD对LTP、APP的损伤不仅起上游前体作用， Aβ效应子。虽然APP作为Aβ前体的作用已经得到了很好的证实，但其作为Aβ效应物的作用才刚刚出现 (and在DS的上下文中根本没有检查）。此外，虽然DS中的APP三倍已经 提示作为DS相关早发性AD的原因，在DS相关LTP损伤中起作用， AD的发病率仍有待研究。在这里，我们将确定APP作为Aβ前体的功能， DS小鼠模型中的效应子。APP敲除可防止Aβ诱导的CaMKII运动损伤 和LTP，我们假设唐氏综合征中APP基因的三重化对 Aβ对CaMKII运动和LTP的影响（甚至在早发性AD表现之前）。我们将在此决定 如果来自DS小鼠模型的海马神经元对Aβ诱导的CaMKII损伤更敏感， 运动，如Aβ暴露剂量或持续时间的较低阈值所反映。后续研究将 研究（i）Aβ诱导的LTP损伤的类似致敏作用，以及（ii）这些作用对 APP的额外拷贝（通过消除DS小鼠系中的APP拷贝之一）。

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).