Stress and CRF Signaling in Alzheimer?s Disease Pathogenesis

阿尔茨海默病发病机制中的应激和 CRF 信号转导

• 批准号: 7898638
• 负责人: Robert A Rissman
• 金额: $ 37.84万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898638
• 关键词: Ablation; Acute; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Animals; Behavioral; Behavioral Assay; Biochemical; Biochemical Process; Brain; Brain region; CRF receptor type 1; Cells; Central Nervous System Diseases; Chronic; Cytoskeletal Proteins; Dependence; Development; Emotional; Emotional Stress; Epidemiologic Studies; Exposure to; Genetic; Genetic Models; Glucocorticoids; Hippocampus (Brain); Human; Immunoelectron Microscopy; Impaired cognition; Label; Learning; Left; Life; Life Stress; Ligands; Longevity; Mediating; Memory; Methods; Modeling; Mus; Neural Pathways; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurotransmitters; Pathogenesis; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Physical Restraint; Physiological; Process; Production; Regimen; Religion and Spirituality; Reporter Genes; Reporting; Risk Factors; Rodent; Role; Severities; Signal Transduction; Signaling Molecule; Site; Source; Specificity; Stress; Structure; System; Testing; Therapeutic Intervention; Transgenic Mice; Work; age related; amyloid pathology; behavior measurement; design; drug development; extracellular; indexing; neural circuit; normal aging; prevent; promoter; public health relevance; repository; research study; response; restraint; restraint stress; stressor; tau Proteins; tau aggregation; tau mutation; tau phosphorylation; tau-1; tau-protein kinase; urocortin

DESCRIPTION (provided by applicant): Stress is implicated as a contributing factor in age-related neurodegenerative disorders such as Alzheimer's Disease (AD), which is defined by the accumulation of plaques composed of ¿-amyloid (A¿) and neurofibrillary tangles consisting of hyperphosphorylated forms of the cytoskeletal protein, tau. The means by which stress contributes to these AD hallmarks remain to be elucidated. We have found that acute exposure to an emotional stressor (physical restraint) elicits robust increases in tau phosphorylation (tau-P) in mouse hippocampus, a pivotal structure in learning and memory. We fail to implicate stress-induced glucocorticoid secretion in this respect, but find the response is abolished by disruption of signaling via the type 1 corticotropin-releasing factor receptor (CRFR1) and exaggerated in CRFR2-deficient mice. Moreover, while acute restraint-induced increments in hippocampal tau-P were short-lived, repeated daily stress sessions (14 days) led to cumulative increases in tau-P and its sequestration in insoluble, pre-pathogenic form. Five aims employing a range of biochemical, histochemical/neuroanatomical and behavioral assays are proposed to further explore the role of stress and the CRF signaling system in mechanisms of AD pathogenesis. First, we will determine whether acute restraint-induced tau-P generalizes to other brain regions afflicted in AD, other stressors that differ in potency and kind, and probe the biochemical mechanisms underlying the response. Second, to define the underlying circuitry, we will characterize sites of stress-induced tau-P (and cellular activation) using transgenic mice that report CRFR expression, use combined retrograde tracing and histochemical methods to identify sources of CRF ligand-containing inputs to hippocampus, and then test experimentally the involvement of implicated neural pathways. Third, we will characterize the effects of repeated exposure to emotional stress on tau-P and A¿ production, and explore their mechanisms and CRFR-dependence. Immunoelectron microscopy will be used to pursue preliminary evidence that repeated stress results in the formation of pre-pathogenic tau aggregates. Fourth, we will assess the ability of stress exposure over a significant portion of lifespan to modulate histochemical, biochemical and behavioral indices of tau and A¿ pathogenesis in a murine model of AD, as well as in normal aging, and determine the CRFR-dependence of observed effects. Finally, we will take advantage of a unique repository of brain material from human AD patients thoroughly characterized antemortem on indices of stress sensitivity and cognitive impairment to determine how the expression of CRF signaling molecules is altered in AD, and the extent to which such alterations may correlate with behavioral measures. The results are expected to clarify (1) the capacity of emotional stress exposure to promulgate AD- related tau and A¿ pathogenesis, (2) the neural circuitry and biochemical mechanisms underlying such effects, and (3) the extent to which they are mediated/modulated by signaling through CRFRs, which may well prove to warrant consideration as targets for therapeutic intervention in AD. PUBLIC HEALTH RELEVANCE Alzheimer's Disease is a progressive, age-related neurodegenerative disorder affecting memory and other higher brain functions, which currently afflicts roughly five million Americans. This project builds on our recent finding that a key biochemical process involved in Alzheimer's Disease can be stimulated by single or repeated exposures to stresses of the kind encountered in everyday life, and that blocking a particular neurotransmitter system in the brain can eliminate this potentially deleterious effect of stress. In deepening understanding of the brain circuits and mechanisms underlying these effects, the proposed experiments will evaluate a legitimate candidate target for the development of drugs that may slow or prevent the progression of Alzheimer's Disease.

描述（由申请人提供）：应激是与年龄相关的神经退行性疾病如阿尔茨海默病（AD）的一个促成因素，阿尔茨海默病的定义是由β-淀粉样蛋白（A β）组成的斑块和由细胞骨架蛋白tau的过度磷酸化形式组成的神经元缠结的积累。压力导致这些AD标志的方式仍有待阐明。我们已经发现，急性暴露于情绪应激源（身体约束）会导致小鼠海马中tau磷酸化（tau-P）的强烈增加，这是学习和记忆的关键结构。我们没有牵连在这方面的应激诱导的糖皮质激素分泌，但发现该反应是通过1型促肾上腺皮质激素释放因子受体（CRFR 1）的信号中断，并夸大CRFR 2缺陷小鼠被取消。此外，虽然急性限制诱导的海马tau-P增量是短暂的，重复的每日应激会话（14天）导致tau-P的累积增加，其螯合在不溶性的，致病前的形式。五个目标采用一系列的生化，组织化学/神经解剖和行为分析，提出进一步探讨应激和CRF信号系统在AD发病机制中的作用。首先，我们将确定急性限制诱导的tau-P是否适用于AD患者的其他大脑区域，其他强度和种类不同的压力源，并探索反应背后的生化机制。其次，为了定义潜在的电路，我们将使用报告CRFR表达的转基因小鼠来表征应激诱导的tau-P（和细胞活化）的位点，使用结合的逆行追踪和组织化学方法来识别含CRF配体的海马输入的来源，然后通过实验测试牵连的神经通路的参与。第三，我们将描述反复暴露于情绪应激对tau-P和A？产生的影响，并探讨其机制和CRFR依赖性。免疫电子显微镜将被用来追求的初步证据表明，反复的压力导致形成的前致病性tau聚集体。第四，我们将评估在寿命的重要部分的应激暴露的能力，以调节组织化学，生物化学和行为指标的tau和A？发病机制在AD的小鼠模型，以及在正常老化，并确定CRFR依赖性的观察到的效果。最后，我们将利用一个独特的存储库的大脑材料从人类AD患者彻底特点生前的压力敏感性和认知障碍的指数，以确定CRF信号分子的表达是如何改变的AD，以及在何种程度上这种改变可能与行为措施。预期结果将阐明（1）情绪应激暴露传播AD相关tau和A？发病机制的能力，（2）此类效应背后的神经回路和生化机制，以及（3）它们通过CRFR信号传导介导/调节的程度，这可能很好地证明值得考虑作为AD治疗干预的靶标。 阿尔茨海默氏病是一种渐进性的、与年龄相关的神经退行性疾病，影响记忆和其他高级大脑功能，目前约有500万美国人患有这种疾病。这个项目建立在我们最近的发现基础上，即阿尔茨海默病中涉及的一个关键的生化过程可以通过单次或重复暴露于日常生活中遇到的那种压力来刺激，并且阻断大脑中特定的神经递质系统可以消除这种潜在的有害影响。为了加深对这些影响背后的大脑回路和机制的理解，拟议的实验将评估一个合理的候选目标，用于开发可能减缓或预防阿尔茨海默病进展的药物。