CaMKII nitrosylation in the age-related decline of synaptic plasticity

认知能力下降主要影响一般老龄化人群的生活质量; 神经退行性疾病的风险增加。一般认为，与年龄相关的认知能力下降 主要是由于突触功能受损，而不是神经元的损失。同样，虽然神经退行性疾病 涉及神经元的损失，在存活的神经元中也存在显著受损的突触功能， 例如，淀粉样蛋白β寡聚体（A β）是阿尔茨海默病（AD）主要病理因子， 海马兴奋性突触长时程增强（LTP）的急性损伤，即使在 点和浓度不足以诱导任何显著的神经元细胞死亡。在这里，我们将测试我们的 假设LTP损伤与正常衰老相对于AD（i）都涉及对LTP的错误调节， Ca2 +/钙调素（CaM）依赖性蛋白激酶II（CaMKII），但（ii）通过根本不同的机制， (iii)导致正常老化与AD中不同形式的LTP损伤。具体来说，我们假设， CaMKII亚亚硝基化直接导致衰老损伤，而不是A β诱导的损伤 （其甚至可替代地涉及超亚硝基化）。此外，我们假设亚亚硝基化 通过对突触成分（包括CaMKII本身）的慢性长期影响降低LTP，而A β影响 而是涉及CaMKII急性错误调节。 众所周知，LTP需要CaMKII及其由Ca2+产生的非Ca2+依赖性"自主"活性， T286的自磷酸化。此外，产生自主活动的两种替代方法是 与NMDA受体亚基GluN2B的结合和C280 + C289的S-亚硝基化。的确， CaMK Ⅱ与GluN2B的结合也是正常LTP和CaMK Ⅱ向兴奋性突触运动所必需的 在LTP期间。CaMKII亚硝酰化在LTP和其他形式的突触可塑性中的功能将被阐明 这里.有趣的是，以前的研究表明，衰老伴随着神经元的亚亚硝基化， 蛋白质，包括CaMKII，在小鼠和人类。此外，初步研究表明， 亚硝基化导致CaMKII运动到兴奋性突触，这需要调节CaMKII结合 GluN2B即LTP诱导的CaMKII运动所需的相同机制。 在三个相关但独立的目标中，我们的建议将确定CaMKII的具体参与 与正常衰老相关的LTP损伤中的亚硝基化与AD相比（预期从根本上 不同的CaMKII错误调节）。首先，我们将确定突触CaMKII的调节机制， 通过亚硝基化定位。然后，我们将确定CaMK II亚硝基化在不同的细胞中的功能， 与正常衰老相比，AD患者LTP受损。最后，我们将确定CaMKII的影响， 亚硝基化对行为任务中学习记忆功能的影响。

Cognitive decline majorly affects quality of life in the general aging population; this is further exacerbated by an increased risk for neurodegenerative diseases. The general age-related cognitive decline is thought to be mainly due to impaired synaptic function, not loss of neurons. Similarly, while neurodegenerative diseases do involve loss of neurons, there is also significantly impaired synaptic function in the surviving neurons, For instance, amyloid β oligomers (Aβ) are major pathological agents in as Alzheimer's disease (AD) and cause acute impairments in long-term potentiation (LTP) of excitatory synapses in the hippocampus, even at time points and concentrations insufficient to induce any significant neuronal cell death. Here we will test our hypotheses that the LTP impairments related to normal aging versus AD (i) both involve mis-regulation of the Ca2+/calmodulin(CaM)-dependent protein kinase II (CaMKII), but (ii) by fundamentally different mechanisms to (iii) result in the distinct forms of LTP impairment in normal aging versus AD. Specifically, we hypothesize that CaMKII hypo-nitrosylation directly causes the impairments in aging, but not the Aβ-induced impairments (which may instead even involve hyper-nitrosylation). Additionally, we hypothesize that hypo-nitrosylation reduces LTP by chronic long-term effects on synapse composition (including CaMKII itself), while the Aβ effects instead involve acute mis-regulation of CaMKII. LTP is well-known to require CaMKII and its Ca2+-independent “autonomous” activity that is generated by autophosphorylation of T286. Additionally, two alternative ways to generate autonomous activity have been described by my lab: Binding to the NMDA-receptor subunit GluN2B and S-nitrosylation of C280+C289. Indeed, CaMKII binding to GluN2B is also required for normal LTP and for the CaMKII movement to excitatory synapses during LTP. The functions of CaMKII nitrosylation in LTP and other forms of synaptic plasticity will be elucidated here. Intriguingly, previous studies have shown that aging is accompanied by hypo-nitrosylation of neuronal proteins, including CaMKII, in both mice and humans. Additionally, preliminary studies indicated that nitrosylation causes CaMKII movement to excitatory synapses, and that this requires regulated CaMKII binding to GluN2B. i.e. the same mechanism that is required for the LTP-induced CaMKII movement. In three related but independent aims, our proposal will determine the specific involvement of CaMKII nitrosylation in the LTP impairments related to normal aging versus AD (with the expectation for fundamentally distinct CaMKII mis-regulation). First, we will determine the regulatory mechanisms for synaptic CaMKII localization by nitrosylation. Then, we will determine the functions of CaMKII nitrosylation in the distinct impairment of LTP related to normal aging versus AD. Finally, we will determine the effects of CaMKII nitrosylation on learning and memory function in behavioral tasks.