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

基本信息

批准号：
10222559
负责人：
K. Ulrich Bayer
金额：
$ 48.95万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10222559
关键词：
Acute Adult Affect Age-associated memory impairment Aging Alzheimer&apos s Disease Behavior Behavioral Binding Brain Cells Chronic Cognition Excitatory Synapse Goals Hippocampus (Brain)Human Image Impaired cognition Impairment Intrabody Knock-in Mouse Learning Long-Term Effects Long-Term Potentiation Mediator of activation protein Memory Monitor Movement Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors Neurodegenerative Disorders Neurons Pathologic Phosphorylation Prevention Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Quality of life Regulation Risk Synapses Synaptic plasticity Testing Time abeta oligomer age related aged aging population calmodulin-dependent protein kinase II expectation improved mutant negative affect neuron loss normal aging novel therapeutic intervention protein transport synaptic function

项目摘要

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.

认知能力下降主要影响一般老龄化人口的生活质量；与年龄相关的认知能力下降被认为是神经退行性疾病的风险增加。主要是由于突触功能受损，而不是神经元损失，而神经退行性疾病却是这样。涉及神经元损失，幸存神经元的突触功能也明显受损，对于例如，β淀粉样蛋白寡聚体 (Aβ) 是阿尔茨海默氏病 (AD) 的主要病理因素，并导致海马兴奋性突触长时程增强（LTP）的急性损伤，甚至在时间上点和浓度不足以诱导任何显着的神经元细胞死亡。假设与正常衰老相关的 LTP 损伤与 AD 相关 (i) 都涉及神经元的错误调节 Ca2+/钙调蛋白 (CaM) 依赖性蛋白激酶 II (CaMKII)，但是 (ii) 通过根本不同的机制 (iii) 与 AD 相比，正常衰老过程中会导致不同形式的 LTP 损伤。 CaMKII 低亚硝基化直接导致衰老损伤，但不是 Aβ 引起的损伤（这甚至可能涉及高亚硝基化）。 LTP 通过对突触组成（包括 CaMKII 本身）的长期长期影响而减少，而 Aβ 则影响相反，涉及 CaMKII 的严重错误调节。众所周知，LTP 需要 CaMKII 及其独立于 Ca2+ 的“自主”活性，该活性由此外，有两种产生自主活性的替代方法。我的实验室描述：与 NMDA 受体亚基 GluN2B 结合和 C280+C289 的 S-亚硝基化。 CaMKII 与 GluN2B 的结合也是正常 LTP 和 CaMKII 运动至兴奋性突触所必需的 LTP 期间 CaMKII 亚硝基化的功能和其他形式的突触可塑性将得到阐明。有趣的是，之前的研究表明，衰老伴随着神经元的低亚硝基化。此外，初步研究表明，包括 CaMKII 在内的小鼠和人类体内的蛋白质。亚硝基化导致 CaMKII 运动到兴奋性突触，这需要受调节的 CaMKII 结合到 GluN2B，即 LTP 诱导的 CaMKII 运动所需的机制相同。在三个相关但独立的目标中，我们的提案将确定 CaMKII 的具体参与与正常衰老相关的 LTP 损伤与 AD 相关的亚硝基化（预计从根本上首先，我们将确定突触 CaMKII 的调节机制。然后，我们将确定 CaMKII 亚硝基化的功能。与正常衰老和 AD 相关的 LTP 损害最后，我们将确定 CaMKII 的影响。亚硝基化对行为任务中学习和记忆功能的影响。