Mechanisms and Treatment of Network Dysfunction in Alzheimer's Disease

描述(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，就有大约500万人患有阿尔茨海默病，这是一种无情的致命疾病，会摧毁精神，并在照顾者中产生绝望的感觉。寻找治疗AD的方法的紧迫性从未像现在这样强烈。AD与癫痫的发生率增加以及认知功能下降有关。癫痫发作和亚临床兴奋性神经元活动可能导致认知障碍。我们建议研究神经保护策略，以对抗AD患者的神经元过度兴奋和癫痫发作，并确定可以从此类治疗中受益的人群。实验室研究的重点是密切调控神经元活动的两个细胞成分-线粒体和电压门控钾通道Kv1.1的轴突运输。神经毒肽淀粉样蛋白(A)损害了线粒体的轴突运输，而微管相关蛋白tau的减少则完全消除了这一作用。在AD转基因小鼠模型中，tau的减少也可以预防癫痫发作和行为缺陷。这些发现提示A？和tau的致病机制涉及轴突运输和神经元兴奋性。在目标1中，我们将研究tau和Aβ调节线粒体和Kv1.1轴突运输的机制，并在AD小鼠模型中研究tau还原对这些物质轴突运输的影响。目的2是一项关于轻度认知障碍和AD患者亚临床癫痫样活动程度的翻译临床研究，着眼于未来使用抗癫痫药物或tau靶向策略的治疗试验。候选人是一名内科科学家，对学术神经学的职业生涯有着坚定的承诺，专注于寻找治疗AD和相关痴呆的新疗法。应聘者拥有生物医学工程硕士学位和神经学临床培训以及行为神经学和神经退行性痴呆的子专业培训的MD学位。研究建议和职业发展计划建立在他在神经科学、衰老和神经退行性疾病方面的培训基础上，以提供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译临床试验方面的专业知识。伦纳特·穆克博士是候选人的赞助人，他是一名内科科学家，照顾痴呆症患者，专门研究神经退行性疾病的转基因小鼠模型。这份提案中描述的指导和研究经验将有助于候选人实现发展强大的独立研究事业的目标。

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.