Oxidative damage and neural signaling in aging

描述(申请人提供)：氧化应激可能会改变老年大脑中的神经元功能，并通过改变神经元内部和神经元之间的交流而导致与年龄相关的认知能力下降。了解认知老化的神经表现可能会导致潜在的药物治疗，旨在减轻与年龄相关的认知衰退。这项拟议的研究将直接检查老年大脑中特定参与神经信号传递的蛋白质的氧化状态。具体地说，在大鼠和人类中，由于衰老而改变的第二个信使系统是磷脂酰肌醇(Pl)的代谢。在老年大鼠中，M受体和代谢性谷氨酸受体对PI翻转的刺激在海马区被钝化，并且在有记录的记忆障碍的老年大鼠中被钝化。在这些大鼠中，也证实了对海马区蛋白质的氧化损伤，但这些蛋白质的身份尚未明确。拟议的实验将试图通过检测与PI周转有关的两个信号蛋白GQ/11和PLC-Beta1的功能和氧化状态来确定与认知衰老相关的PI周转障碍的分子位置。利用空间学习能力评估过的年轻和老年大鼠的海马区组织，该项目将解决以下具体目标：1)GQ/11和PLC-β1是否保持其刺激认知障碍老年大鼠海马区PI周转的能力？2)海马区的M受体和代谢型谷氨酸受体偶联是否随年龄改变，纹状体和额叶皮质？3)GQ/11和PLC-β1在老年大鼠的海马区是否发生氧化损伤？这种损伤是否与认知障碍有关？4)GQ/11和PLC-β1发生的与年龄相关的变化能否通过在体外通过实验诱导年轻动物海马区的氧化应激来复制？如果是这样的话，这个模型随后将被用来测试抗氧化剂防止GQ/11和/或PLC-Beta1功能的氧化损伤的有效性。这些研究有可能揭示与年龄相关的PI功能障碍的分子位置、功能障碍的原因，以及特定蛋白质的氧化损伤与认知障碍之间的联系。

DESCRIPTION (provided by applicant): Oxidative stress may alter neuron function in the aged brain and contribute to age-related cognitive decline by altering communication within and between neurons. Understanding the neural manifestation of cognitive aging may lead to potential pharmacological therapies intended to attenuate age-related cognitive decline. The proposed research will directly examine the oxidative status of proteins specifically involved in neural signaling in the aged brain. Specifically, a second messenger system that is altered as a consequence of aging in both rats and humans is phosphoinositide (Pl) turnover. In aged rats, muscarinic and metabotropic glutamate receptor stimulation of PI turnover is blunted in the hippocampus, and is most blunted in aged rats with documented memory impairment. In these same rats, oxidative damage to hippocampal proteins has also been demonstrated, but the identity of these proteins has not been specified. The proposed experiments will attempt to identify the molecular site of PI turnover dysfunction that is associated with cognitive aging by examining the function and oxidative status of two signaling proteins coupled to PI turnover, Gq/11 and PLC-beta1. Using hippocampal tissue from young and aged rats that have been assessed for spatial learning ability, this project will address the following specific aims: 1) Do Gq/11 and PLC-beta1 maintain their ability to stimulate PI turnover in the hippocampus of aged rats with cognitive impairment? 2) Is muscarinic and metabotropic glutamate receptor coupling altered with age in the hippocampus, striatum and frontal cortex? 3) Are Gq/11 and PLC-beta1 oxidatively damaged in the hippocampus of the aged rat and does this damage correlate with cognitive impairment? 4) Can the age-related alterations that occur to Gq/11 and PLC-beta1 be replicated by experimentally inducing oxidative stress in the hippocampus of a young animal in vitro? If so, this model will subsequently be used to test the efficacy of antioxidants to prevent oxidative damage to Gq/11 and/or PLC-beta1 function. These studies have the potential to show the molecular site of age-related PI dysfunction, the cause of the dysfunction, and a linkage between oxidative damage to specific proteins and cognitive impairment.