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人口的生活质量；这进一步加剧了