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（由申请人提供）：阿尔茨海默病 (AD) 和其他与年龄相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，就有约 500 万人患有 AD，这是一种严重破坏精神和健康的致命疾病。寻找 AD 治疗方法的紧迫性与癫痫发作以及认知能力下降有关。兴奋性神经活动可能导致认知缺陷。我们建议研究神经保护策略，以对抗 AD 中的神经元过度兴奋和癫痫发作，并确定可以从此类疗法中受益的人群。实验室研究的重点是严格调节神经元的两种细胞成分的轴突运输。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¿) 损害线粒体的轴突运输，并且微管相关蛋白 tau 的减少完全消除了这种效应，还可以防止 AD 转基因小鼠模型中的癫痫发作和行为缺陷。这些发现表明 A¿在目标 1 中，我们将研究 tau 和 A¿ 的机制。调节线粒体和 Kv1.1 的轴突运输，并在 AD 小鼠模型中研究 tau 蛋白减少对这些货物体内轴突运输的影响。 Aim 2 是一项针对 AD 患者亚临床癫痫样活动程度的转化临床研究。轻度认知障碍和 AD，着眼于未来使用抗癫痫药物或 tau 靶向策略的治疗试验 该候选人是一位致力于学术神经病学职业的医师科学家。该候选人拥有生物医学工程硕士学位和神经病学临床培训以及行为神经病学和神经退行性痴呆亚专业培训的医学博士学位，该研究计划和职业发展计划建立在他的神经科学培训的基础上。衰老和神经退行性疾病，提供 AD 转基因小鼠模型、组织学、细胞培养、微流体室、延时显微镜、经颅双光子成像和转化临床试验方面的专业知识。 Lennart Mucke 博士是一位治疗痴呆症患者的医师科学家，专门研究神经退行性疾病的转基因小鼠模型，该提案中描述的指导和研究经验将促进候选人发展强大的独立研究的目标。职业。 公共健康相关性：随着美国人口老龄化，痴呆症患病率预计将增加，这对我们的医疗保健系统构成重大威胁，开发新的治疗方法是该项目的一个关键目标，旨在揭示 tau 蛋白减少的机制。对 AD 小鼠模型中的神经网络和癫痫发作具有保护作用，并可识别处于 AD 早期阶段、具有功能障碍的亚临床癫痫样活动的人群，以及哪些人群可以从 tau 靶向策略或抗癫痫药物 A 宿主中受益。 FDA 批准的抗癫痫药物已经上市，可以在未来的临床试验中进行测试。