CaMKII nitrosylation in the age-related decline of synaptic plasticity

认知下降主要影响一般老龄化人口的生活质量；这一点进一步加剧 增加神经退行性疾病的风险。一般认为，与年龄相关的认知能力下降是 主要是由于突触功能受损，而不是神经元的丧失。同样，尽管神经退行性疾病会 涉及神经元的丧失，存活的神经元也有显著的突触功能受损， 例如，淀粉样蛋白β寡聚体(Aβ)是阿尔茨海默病(AD)的主要病原体和病因 海马区兴奋性突触长时程增强(LTP)的急性损害，即使在 不足以导致任何显著神经细胞死亡的点和浓度。在这里我们将测试我们的 LTP损伤与正常衰老和AD相关的假说(I)都涉及对 Ca2/钙调蛋白(CaM)依赖的蛋白激酶II(CaMKII)，但(Ii)通过根本不同的机制 (3)在正常衰老与AD相比，导致不同形式的LTP损伤。具体地说，我们假设 CaMKII亚硝化直接导致衰老损伤，而不是A-β诱导的损伤 (相反，这甚至可能涉及高亚硝酸化)。此外，我们假设次亚硝化反应 通过对突触成分(包括CaMKII本身)的慢性长期影响而减少长时程增强，而Aβ影响 相反，它涉及对CaMKII的严重不当调控。 众所周知，LTP需要CaMKII及其不依赖于钙的“自主”活动，这种活动是由 T286的自身磷酸化。此外，产生自主活动的两种替代方式是 我的实验室描述：与C280 C289的Nmda受体亚单位GluN2B结合和S亚硝化。的确， CaMKII与GluN2B的结合也是正常LTP和CaMKII向兴奋性突触运动所必需的 在LTP期间。CaMKII亚硝化在LTP和其他形式的突触可塑性中的作用将被阐明 这里。有趣的是，先前的研究表明，衰老伴随着神经元的亚硝酸化。 包括CaMKII在内的蛋白质，在老鼠和人类中都是如此。此外，初步研究表明， 亚硝化导致CaMKII运动到兴奋性突触，这需要调节的CaMKII结合 致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，我们的提案将决定CAMKII的具体参与 与AD相比，与正常衰老相关的LTP损伤中的亚硝酸化(期望从根本上 明显的CaMKII不当监管)。首先，我们将确定突触CaMKII的调节机制 亚硝化法定位。然后，我们将确定CaMKII亚硝化在不同的 与AD相比，LTP受损与正常衰老有关。最后，我们将确定CaMKII的效果 亚硝酸酯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.