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: 10454912
• 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/10454912
• 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群的生活质量；这种情况进一​​步加剧 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是 主要是由于突触功能受损，而不是神经元损失。同样，虽然神经退行性疾病确实 涉及神经元损失，幸存神经元的突触功能也显着受损，对于 例如，β淀粉样蛋白寡聚体 (Aβ) 是阿尔茨海默氏病 (AD) 的主要病理因子，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。在这里我们将测试我们的 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。具体来说，我们假设 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）。此外，我们假设低亚硝基化 通过对突触组成（包括 CaMKII 本身）的长期影响来降低 LTP，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 T286 的自身磷酸化。此外，产生自主活动的两种替代方法是 我的实验室描述：与 NMDA 受体亚基 GluN2B 结合以及 C280+C289 的 S-亚硝基化。的确， 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 在 LTP 期间。 CaMKII 亚硝基化在 LTP 和其他形式的突触可塑性中的功能将得到阐明 这里。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。 小鼠和人类体内的蛋白质，包括 CaMKII。此外，初步研究表明 亚硝基化导致 CaMKII 运动到兴奋性突触，这需要受调节的 CaMKII 结合 至 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 明显的 CaMKII 错误调节）。首先，我们将确定突触CaMKII的调节机制 通过亚硝基化进行定位。然后，我们将确定 CaMKII 亚硝基化在不同的 与正常衰老相关的 LTP 损伤与 AD 相比。最后，我们将确定 CaMKII 的效果 亚硝基化对行为任务中学习和记忆功能的影响。