Mechanisms and Treatment of Network Dysfunction in Alzheimer's Disease

阿尔茨海默病网络功能障碍的机制和治疗

• 批准号: 8189497
• 负责人: Keith Alan Vossel
• 金额: $ 15.28万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189497
• 关键词: Acute; Affect; Age; Aging; Alzheimer' s Disease; American; Americas; Amyloid; Amyloid beta-Protein Precursor; Antiepileptic Agents; Axonal Transport; Behavioral; Biological Neural Networks; Biomedical Engineering; Brain; Caregivers; Cell Culture Techniques; Clinical; Clinical Research; Clinical Trials; Cognitive; Cognitive deficits; Defect; Dementia; Deposition; Development; Development Plans; Disease; Electroencephalography; Epilepsy; Eye; FDA approved; Feeling; Feeling hopeless; Frequencies; Frontotemporal Dementia; Functional disorder; Future; Genetic; Goals; Healthcare Systems; Hippocampus (Brain); Histology; Human; Image; Impaired cognition; Impairment; Incidence; Investigation; KCNA1 channel; Laboratories; Lewy Body Disease; Magnetoencephalography; Memory; Mentors; Microfluidics; Microscopy; Mind; Mitochondria; Monitor; Morbidity - disease rate; Mus; Nerve Degeneration; Nerve Growth Factor Receptors; Neurodegenerative Disorders; Neurology; Neurons; Neurosciences; Participant; Pathogenesis; Pathology; Pathway interactions; Patient Care; Patients; Peptides; Pharmaceutical Preparations; Physicians; Population; Prevalence; Research; Research Proposals; Scientist; Seizures; Source; Staging; Subclinical Seizures; Synapses; Systems Development; Testing; Therapeutic; Therapy Clinical Trials; Time; Training; Transgenic Mice; Voltage-Gated Potassium Channel; age related; amyloid formation; amyloid peptide; base; career; career development; design; experience; follow-up; in vivo; mild neurocognitive impairment; mortality; mouse model; network dysfunction; neurodegenerative dementia; neuronal excitability; neurotoxic; novel; novel therapeutic intervention; prevent; protein expression; small hairpin RNA; tau Proteins; tau expression; translational clinical trial; two-photon

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) and other age-related neurodegenerative disorders are a major source of morbidity and mortality. In the U.S. alone, some 5 million people have AD, a relentless and fatal condition that devastates the mind and engenders feelings of hopelessness in caregivers. The urgency in finding a cure for AD has never been stronger. AD is associated with an increased incidence of seizures as well as cognitive decline. Seizures and subclinical excitatory neuronal activity may contribute to cognitive deficits. We propose to investigate neuroprotective strategies to counter neuronal overexcitation and seizures in AD and identify a population who could benefit from such therapies. The laboratory investigation focuses on the axonal transport of two cellular components that tightly regulate neuronal activity-mitochondria and the voltage-gated potassium channel Kv1.1. The neurotoxic peptide amyloid-¿ (A¿) impairs axonal transport of mitochondria, and reduction of the microtubule-associated protein tau completely abolishes this effect. Tau reduction also protects against seizures and behavioral deficits in transgenic mouse models of AD. These findings suggest a pathogenic mechanism for A¿ and tau involving axonal transport and neuronal excitability. In Aim 1, we will investigate mechanisms by which tau and A¿ regulate the axonal transport of mitochondria and Kv1.1, and study the effects of tau reduction on axonal transport of these cargoes in vivo in a mouse model of AD. Aim 2 is a translational clinical investigation of the extent of subclinical epileptiform activity in people with mild cognitive impairment and AD with an eye toward future therapeutic trials using antiepileptic medications or tau-targeted strategies. The candidate is a physician-scientist with a strong commitment to a career in academic neurology focused on identifying novel therapies for AD and related dementias. The candidate has an MSc in biomedical engineering and an MD with clinical training in neurology and subspecialty training in behavioral neurology and neurodegenerative dementias. The research proposal and career development plan build upon his training in neuroscience, aging, and neurodegenerative diseases to provide expertise in transgenic mouse models of AD, histology, cell culture, microfluidics chambers, time-lapse microscopy, transcranial two-photon imaging, and translational clinical trials. Dr. Lennart Mucke, a physician-scientist who cares for patients with dementia and specializes in transgenic mouse models of neurodegenerative disease, is the candidate's sponsor. The mentoring and research experience described in this proposal will facilitate the candidate's goal of developing a strong independent research career. PUBLIC HEALTH RELEVANCE: Projected increases in the prevalence of dementia with the aging of the American population are a major threat to our healthcare system, and the development of novel therapeutic approaches is a critical goal. This project is designed to uncover mechanisms by which tau reduction is protective against neural network dysfunction and seizures in mouse models of AD and to identify people in the early stages of AD who have subclinical epileptiform activity and who could benefit from tau-targeted strategies or antiepileptic drugs. A host of FDA-approved antiepileptic medications are already available that could be tested in future clinical trials.

描述（由适用提供）：阿尔茨海默氏病（AD）和其他与年龄有关的神经退行性疾病是发病率和死亡率的主要来源。仅在美国，大约有500万人有广告，这种友好而致命的状况破坏了思想，并使看护者的绝望感使人感到绝望。寻找AD治疗的紧迫性从未有过强大。 AD与癫痫发作的增加以及认知能力下降有关。癫痫发作和亚临床兴奋神经元活性可能导致认知缺陷。我们建议研究神经保护策略，以抵抗AD中神经元过度兴奋和癫痫发作，并确定可以从这种疗法中受益的人群。实验室研究的重点是两个细胞成分的轴突转运，这些细胞成分紧密调节神经元活性线粒体和电压门控钾通道KV1.1。神经毒性肽淀粉样蛋白 - （a¿）会损害线粒体的轴突转运，而微管相关蛋白tau的还原完全消除了这种效果。 tau还原还可以防止AD的转基因小鼠模型中的癫痫发作和行为缺陷。这些发现提出了一种涉及轴突转运和神经元令人兴奋的A和TAU的致病机制。在AIM 1中，我们将研究Tau​​和A调节线粒体和KV1.1的轴突运输的机制，并研究tau还原对这些货物在Vivo中轴突转运的影响。 AIM 2是对患有轻度认知障碍者亚临床癫痫病活性程度的翻译临床研究，并着眼于使用抗癫痫药或tau靶向策略的未来治疗试验。候选人是一位身体科学家，对学术神经病学职业的坚定承诺致力于识别针对AD和相关痴呆症的新疗法。该候选人拥有生物医学工程的硕士学位和MD的MD，并在行为神经病学和神经退行性痴呆症方面的神经病学和专科培训进行了临床培训。研究建议和职业发展计划基于他在神经科学，衰老和神经退行性疾病方面的培训，以在AD，组织学，细胞培养，微流体室，延时显微镜，经颅两光子成像和翻译临床试验的转基因小鼠模型中提供专业知识。伦纳特·穆克（Lennart Mucke）博士是一位身体科学家，他是痴呆症患者，专门研究神经退行性疾病的转基因小鼠模型，是候选人的赞助商。该提案中描述的心理和研究经验将有助于候选人发展强大的独立研究职业的目标。 公共卫生相关性：痴呆症患病率的预计随着美国人群的衰老而预计增加是对我们的医疗保健系统的主要威胁，而新型治疗方法的发展是一个关键目标。该项目旨在发现AD小鼠模型中的神经网络功能障碍和癫痫发作的机制，并在AD的早期阶段鉴定患有亚临床性癫痫样活动的人，并且可以从Tau-Target的策略或抗癫痫药中受益。已经可以在将来的临床试验中测试了许多经FDA批准的抗癫痫药。