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: 8105068
• 负责人: Robert A Rissman
• 金额: $ 36.37万
• 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/8105068
• 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; Disease; Emotional; Emotional Stress; Epidemiologic Studies; Exposure to; Genetic; Genetic Models; Glucocorticoids; Health; 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; Pathology; 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; Systemic disease; Testing; Therapeutic Intervention; Transgenic Mice; Work; age related; behavior measurement; design; drug development; extracellular; indexing; neural circuit; normal aging; prevent; promoter; 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）：压力是与年龄相关的神经退行性疾病（例如阿尔茨海默氏病（AD））的一个促成因素，其定义是由β-淀粉样蛋白（Aβ）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原纤维缠结的积累。压力导致这些 AD 特征的方式仍有待阐明。我们发现，急性暴露于情绪压力源（身体束缚）会引起小鼠海马体中 tau 蛋白磷酸化 (tau-P) 的急剧增加，海马体是学习和记忆的关键结构。我们未能在这方面暗示应激诱导的糖皮质激素分泌，但发现该反应因 1 型促肾上腺皮质激素释放因子受体 (CRFR1) 信号传导的破坏而被消除，并且在 CRFR2 缺陷小鼠中加剧。此外，虽然急性约束引起的海马 tau-P 增加是短暂的，但每天重复的应激训练（14 天）会导致 tau-P 累积增加，并以不溶性、致病前形式被隔离。提出了采用一系列生化、组织化学/神经解剖学和行为测定的五个目标，以进一步探索应激和 CRF 信号系统在 AD 发病机制中的作用。首先，我们将确定急性约束诱导的 tau-P 是否会普遍影响 AD 患者的其他大脑区域以及其他效力和种类不同的压力源，并探讨该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（和细胞激活）位点，使用逆行追踪和组织化学相结合的方法来识别海马体中含有 CRF 配体的输入来源，然后通过实验测试所涉及的神经通路的参与。第三，我们将描述反复暴露于情绪压力对 tau-P 和 A¿ 产生的影响，并探讨其机制和 CRFR 依赖性。免疫电子显微镜将用于寻找初步证据，证明反复应激会导致致病前 tau 蛋白聚集体的形成。第四，我们将评估在 AD 小鼠模型以及正常衰老中，在生命周期的很大一部分时间里，压力暴露调节 tau 和 A¿ 发病机制的组织化学、生化和行为指数的能力，并确定观察到的效果的 CRFR 依赖性。最后，我们将利用人类 AD 患者大脑材料的独特存储库，在生前彻底表征压力敏感性和认知障碍指数，以确定 CRF 信号分子的表达在 AD 中如何改变，以及这种改变与行为测量的相关程度。这些结果预计将阐明（1）情绪压力暴露对揭示 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）CRFR 信号传导/调节它们的程度，这很可能证明值得考虑作为 AD 治疗干预的目标。 公共健康相关性 阿尔茨海默病是一种进行性、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。该项目建立在我们最近的发现之上，即与阿尔茨海默氏病有关的一个关键生化过程可以通过单次或重复暴露于日常生活中遇到的压力来刺激，并且阻断大脑中的特定神经递质系统可以消除压力的这种潜在有害影响。为了加深对这些影响背后的大脑回路和机制的理解，拟议的实验将评估开发可能减缓或预防阿尔茨海默病进展的药物的合法候选靶点。