The role of protein phosphatase 2A in age-related memory impairment

蛋白磷酸酶2A在年龄相关记忆障碍中的作用

• 批准号: 7472906
• 负责人: MICHAEL A KING
• 金额: $ 18.68万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472906
• 关键词: Accounting; Activating Transcription Factor 2; Age; Age-associated memory impairment; Aging; Animals; Behavioral; Bilateral; Binding; Biochemical; Biological Assay; Brain; Bypass; Cell membrane; Cell physiology; Chronic; Class; Complement; Complex; Comprehension; DNA Binding; Data; Dependovirus; Disruption; Elevation; Enzymes; Evaluation; Exhibits; Extracellular Signal Regulated Kinases; FOS gene; Failure; Gene Delivery; Gene Expression; Gene Transfer; Genes; Genetic Transcription; Glutamates; Green Fluorescent Proteins; Hippocampus (Brain); Impairment; Injection of therapeutic agent; Interruption; Knowledge; Lead; Learning; Localized; Mediating; Memory; Memory Loss; Memory impairment; Mitogen-Activated Protein Kinases; Modeling; Molecular; Neurons; Neurotransmitter Receptor; Nuclear; Numbers; Performance; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiology; Population; Positioning Attribute; Protein Overexpression; Protein Phosphatase Inhibitor; Protein phosphatase; Proteins; Public Health; Rattus; Receptor Activation; Reporting; Role; Sampling; Short-Term Memory; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Synaptic Transmission; System; Techniques; Testing; Tissue Harvesting; Tissue Sample; Up-Regulation; Water; Week; age related; aged; base; concept; experience; extracellular; gene transfer vector; improved; inhibitor/antagonist; inorganic phosphate; metabotropic glutamate receptor 5; receptor; transgene expression; vector

DESCRIPTION (provided by applicant): Variable degrees of memory loss occur during aging, even in otherwise healthy people. Attempts to counteract age-related memory loss (ARML) will benefit from knowledge of the brain mechanisms involved. Many proteins vary in function according to the extent to which phosphate groups are added by kinases or removed by phosphatases. Imbalance in these enzymatic activities can disrupt intracellular signaling pathways necessary to mediate changes in gene expression and cellular function that are required for learning and memory to occur. Protein phosphatase (PP) 2A is the primary enzyme acting on the extracellular receptor kinase (ERK) class of mitogen-activated protein kinases (MAPK). The type 5 metabotropic glutamate neurotransmitter receptor (mGluR5) forms a complex with active PP2A along the neuronal plasma membrane. This complex dissociates when glutamate binds to mGluR5 receptors, inactivating PP2A and allowing the accumulation of the activated, phosphorylated forms of ERK (pERKs). These stimulate levels of nuclear phosphoproteins, such as Elk-1, to form DNA-binding complexes that activate the expression of several genes. Interruption of this signal transduction cascade impairs learning and memory. Reduction in the number of functional mGluR5 receptors, and pERK activity, during aging suggest that ARML may represent a failure of integrated neuronal synaptic transmission to generate a threshold level of intracellular pERK necessary for the expression of memory-related genes. To bypass the lost receptors and boost pERK levels, we propose using a gene delivery technique to overexpress I1PP2A, a natural protein inhibitor of PP2A. A vector based on adeno-associated virus (AAV) will be used for bilateral hippocampal injections in 26-month rats exhibiting an age-related impairment in learning and memory performance. Acquisition and retention of hippocampal-dependent and independent maze tasks will be re-evaluated 4 weeks after I1PP2A or control gene transfer. Hippocampal tissue harvested after gene transfer and behavioral reassessment will be used for histological evaluation of transgene expression. We hypothesize that treatment with I1PP2A will normalize age-impairment. Further, we predict that the improvement in learning and memory will correspond with decreased PP2A activity, increased levels of pERK, and upregulation of downstream targets pElk-1, pCREB, c-fos, zif/268 and arc. PUBLIC HEALTH RELEVANCE: Many people experience a decrease in memory function as they age. The proposed project will test how disruption of one biochemical signaling system in the brain might account for a reduced ability for aged rats to learn or remember. The results could lead to new pharmacological targets for treating age-related memory dysfunction.

描述（由申请人提供）：不同程度的记忆丧失发生在衰老过程中，即使在其他健康的人。对抗年龄相关性记忆丧失（ARML）的尝试将受益于有关大脑机制的知识。许多蛋白质的功能根据磷酸基团被激酶添加或被磷酸酶去除的程度而变化。这些酶活性的不平衡可以破坏细胞内信号传导途径，这些信号传导途径是介导学习和记忆发生所需的基因表达和细胞功能变化所必需的。蛋白磷酸酶（PP）2A是作用于细胞外受体激酶（ERK）类丝裂原活化蛋白激酶（MAPK）的主要酶。5型代谢型谷氨酸神经递质受体（mGluR 5）与活性PP 2A沿着神经元质膜形成复合物。当谷氨酸与mGluR 5受体结合时，该复合物解离，使PP 2A失活并允许ERK（pERK）的活化磷酸化形式的积累。这些刺激水平的核磷蛋白，如Elk-1，形成DNA结合复合物，激活几个基因的表达。这种信号转导级联的中断损害学习和记忆。在衰老过程中，功能性mGluR 5受体和pERK活性的数量减少表明，ARML可能代表整合的神经元突触传递失败，无法产生记忆相关基因表达所需的细胞内pERK阈值水平。为了绕过丢失的受体并提高pERK水平，我们建议使用基因递送技术来过表达PP 2A的天然蛋白抑制剂I1 PP 2A。基于腺相关病毒（AAV）的载体将用于双侧海马注射26个月的大鼠表现出年龄相关的学习和记忆能力的损害。在I1 PP 2A或对照基因转移后4周，将重新评估对海马依赖性和独立性迷宫任务的获得和保持。在基因转移和行为再评估后收获的海马组织将用于转基因表达的组织学评价。我们假设I1 PP 2A治疗可以使年龄损害正常化。此外，我们预测学习和记忆的改善将与PP 2A活性降低、pERK水平升高以及下游靶点pElk-1、pCREB、c-fos、zif/268和arc的上调相对应。公共卫生相关性：随着年龄的增长，许多人的记忆功能会下降。该项目将测试大脑中一个生化信号系统的破坏如何解释老年大鼠学习或记忆能力的下降。这些结果可能会导致治疗年龄相关记忆功能障碍的新药理学靶点。