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: 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
• 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' 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

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；这进一步加剧了 神经退行性疾病的风险增加。一般与年龄相关的认知下降被认为是 主要是由于突触功能受损而不是神经元的丧失。同样，虽然神经退行性疾病确实 涉及神经元的丧失，在幸存的神经元中的突触功能也显着受损，因为 实例，淀粉样蛋白β低聚物（Aβ）是阿尔茨海默氏病（AD）的主要病理剂，并导致 海马中的兴奋性突触长期增强（LTP）的急性损害，即使在时间 点和浓度不足以诱导任何明显的神经元细胞死亡。在这里我们将测试我们的 假设LTP损害与正常衰老与AD（i）有关 Ca2+/钙调蛋白（CAM）依赖性蛋白激酶II（CAMKII），但（ii）从根本上不同的机制与 （iii）导致正常衰老与AD中LTP损伤的不同形式。具体来说，我们假设 CAMKII低亚硝基化直接导致衰老损伤，但不会导致Aβ诱导的损伤 （相反，可能涉及高硝基化）。另外，我们假设低硝基化 通过对突触组成（包括CAMKII本身）的慢性长期影响减少LTP，而Aβ效应 而是涉及camkii的急性不利。 LTP众所周知需要CAMKII及其CA2+独立的“自主”活动，这是由 T286的自磷酸化。此外，已经有两种产生自主活动的替代方法 由我的实验室描述：与NMDA受体亚基Glun2b和C280+C289的S-硝基化结合。的确， 正常的LTP和CAMKII运动也需要与Glun2b结合的CAMKII结合到兴奋性突触 在LTP期间。 LTP和其他形式的突触可塑性在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，先前的研究表明，衰老是通过神经元低硝基化完成的 蛋白质，包括camkii，包括小鼠和人类。此外，初步研究表明 硝基化导致CaMKII运动引起兴奋性突触，这需要调节的CAMKII结合 到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的特定参与 LTP损伤与正常衰老与AD相关的LTP损伤的硝基化（从根本上期望 独特的CAMKII失误）。首先，我们将确定突触CAMKII的调节机制 硝基化定位。然后，我们将确定camkii硝基化的功能 LTP与正常衰老与AD相关的损害。最后，我们将确定Camkii的影响 在行为任务中学习和记忆功能的硝基化。