Mechanism for Altered Synaptic Function During Aging

衰老过程中突触功能改变的机制

• 批准号: 7429744
• 负责人: THOMAS C FOSTER
• 金额: $ 26.49万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429744
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Amino Acids; Animals; Antioxidants; Award; Behavioral; Biochemistry; Biological; Biological Markers; Biological Preservation; Calcineurin; Calcium; Characteristics; Cognitive; Cognitive deficits; Cysteine; Data; Defense Mechanisms; Elements; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Exercise; Figs - dietary; Functional disorder; Gene Delivery; Genes; Genetic Transcription; Hippocampus (Brain); Homeostasis; Impaired cognition; Impairment; Knowledge; Link; Lipid Peroxidation; Lipids; Mediating; Membrane; Memory; Memory impairment; Modeling; N-Methyl-D-Aspartate Receptors; Nucleotides; Oxidation-Reduction; Oxidative Stress; Pharmacological Treatment; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Physiology; Play; Predisposition; Process; Proteins; Reactive Oxygen Species; Reducing Agents; Regulation; Relative (related person); Research; Role; Source; Stress; Subfamily lentivirinae; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Thinking; Vitamin E; Work; age related; age related neurodegeneration; aged; aging brain; base; biochemical model; calcineurin phosphatase; conditioning; disulfide bond; improved; interest; memory process; oxidation; prevent; receptor function; senescence; synaptic depression; synaptic function; therapy design; voltage

DESCRIPTION (provided by applicant): The primary cognitive deficit associated with aging and Alzheimer's disease is impairment of memory processes that require proper hippocampal function. Regulation of Ca2+ is thought to play a role in age-related neurodegeneration and the synaptic plasticity that underlies memory. However, the key elements that link Ca2+ homeostasis with memory or memory impairment remain to be determined. Our work, supported by the preceding award, provides evidence that a decrease in neural transmission through the hippocampus, which is characteristic of age-related memory impairments, results from a shift in susceptibility to induction of synaptic plasticity favoring synaptic depression. The shift in synaptic plasticity is linked to changes in Ca2+ sources with increased contributions from voltage-dependent L-channels and intracellular Ca2+ stores and decreased contributions from NMDA receptors. The Ca2+ dysregulation alters subsequent Ca2+-dependent process, particularly the Ca2+-dependent afterhyperpolarization (AHP), and the activity of the Ca2+-dependent phosphatase, calcineurin, and ultimately gene transcription. In turn, the amplitude of the AHP and level of calcineurin activity regulate synaptic modifiability and are correlated with memory function. Together, these elements provide physiological and biochemical models which link Ca2+ dysregulation to senescent physiology and biochemistry thought to mediate memory. Currently there is a gap in our knowledge concerning the process that leads to Ca2+ dysregulation. Research suggests that oxidative stress can impair Ca2+ homeostasis and synaptic plasticity in a manner similar to that observed during aging. Thus, the current proposal examines oxidative stress as a potential mechanism and target for treatment of Ca2+ dysregulation. Specific aim 1 will employ conditioning treatments which have been shown to reduce oxidative stress and/or improved memory. We will determine if improved memory is associated with changes in Ca2+- dependent processes as predicted by our model. Specific aim 2 will apply pharmacological treatments and gene manipulations to reduce oxidative stress to determine if these treatments modify markers of brain aging and improve memory. Specifc aim 3 will addresses the issue of how oxidative stress contributes to calcium dysregulation during aging in the hippocampus by examining the influence of redox state on Ca2+ dependent processes.

描述（由申请人提供）：与衰老和阿尔茨海默氏病有关的主要认知缺陷是需要适当海马功能的记忆过程的损害。 CA2+的调节被认为在年龄相关的神经变性和基础记忆的突触可塑性中起作用。但是，将Ca2+稳态与内存或内存障碍联系起来的关键元素仍有待确定。我们的工作得到了先前的奖项的支持，这证明了通过海马的神经传播减少，这是与年龄相关的记忆障碍的特征，这是由于诱导突触可抑制突触抑郁症的敏感性的转变而导致的。突触可塑性的转移与Ca2+源的变化有关，其依赖电压依赖性L通道和细胞内Ca2+存储的贡献增加，以及NMDA受体的贡献减少。 CA2+失调症改变了随后的Ca2+依赖性过程，尤其是Ca2+依赖性的无极性（AHP），以及Ca2+依赖性磷酸酶，钙调蛋白，最终基因转录的活性。反过来，AHP的幅度和钙调神经酶活性的水平调节突触可修改性，并与内存功能相关。这些元素共同提供了生理和生物化学模型，这些模型将Ca2+失调与衰老生理学和生物化学联系起来介导记忆。当前，我们的知识存在有关导致CA2+失调过程的过程的差距。研究表明，氧化应激会以类似于衰老期间观察到的方式损害Ca2+稳态和突触可塑性。因此，当前的建议将氧化应激视为一种潜在的机制和治疗Ca2+失调的靶标。特定的目标1将采用条件治疗，这些治疗已被证明可以减少氧化应激和/或改善记忆力。我们将确定改进的内存是否与我们模型预测的Ca2+相关过程的变化相关联。具体目标2将应用药理治疗和基因操纵以减少氧化应激，以确定这些治疗方法是否改变了大脑衰老的标志并改善记忆力。 SPECIFC AIM 3将通过检查氧化还原状态对Ca2+依赖性过程的影响，以解决海马衰老过程中氧化应激如何促进钙失调的问题。