Investigating the role of Alzheimer's disease familial mutations in neuromuscular physiology

研究阿尔茨海默病家族突变在神经肌肉生理学中的作用

• 批准号: 10620712
• 负责人: James J Hickman
• 金额: $ 74.35万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620712
• 关键词: Afferent Neurons; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Animals; Axon; Biological Aging; Biological Assay; Biological Markers; Biological Products; Blood Tests; Brain; Cells; Central Nervous System; Characteristics; Clinic; Clinical; Clinical Markers; Clinical Trials; Cohort Studies; Collaborations; Companions; Complement; Data; Decision Making; Dementia; Deterioration; Development; Diagnostic; Disease; Dose; Drug Screening; Evaluation; Exhibits; Fiber; Gait abnormality; Generations; Grant; Human; Impaired cognition; Institutionalization; Investigation; Link; Longitudinal Studies; Measurement; Modeling; Monitor; Motor; Motor Neurons; Muscle; Muscle Contraction; Muscle Fibers; Mutation; Nervous System Physiology; Neuromuscular Junction; Organ; Outcome; Pathology; Patients; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phenotype; Physiology; Preclinical Testing; Publishing; Reflex action; Risk; Role; Screening procedure; Sensory; Serum; Skeletal Muscle; Spinal; Stretching; System; Task Performances; Tauopathies; Testing; Therapeutic; Toxic effect; Vertebral column; abeta oligomer; animal data; biological systems; biomarker discovery; biomarker identification; clinical biomarkers; clinical predictors; clinically relevant; diagnostic criteria; experience; experimental study; familial Alzheimer disease; functional decline; high risk; human model; improved; in vitro Model; individualized medicine; induced pluripotent stem cell; microphysiology system; mild cognitive impairment; mortality; motor disorder; motor impairment; mutant; neuromuscular; neuron component; neuronal cell body; novel; pre-clinical; response; screening; sensor; sensory system; small molecule; success; tau Proteins; tau aggregation; tool

Project Summary There are few in vitro models that examine Alzheimer’s disease (AD) pathology outside the central nervous system. Several studies have indicated the lack of appropriate preclinical Alzheimer’s Disease and Related Dementias (ADRD) models as one of the barriers for successful development of AD/ADRD therapeutics. Motor impairment is a common feature of early AD pathology and the link between motor function and the risk of developing AD has been increasingly recognized. Gait abnormalities have been found to precede the onset of dementia by many years. It is now becoming apparent that treatment windows and thus clinical trials must shift to the mild cognitive impairment (MCI) or better yet the pre-MCI stage to be effective, however, there are few if any diagnostics to predict who will develop AD at this stage of the disease. Studies have demonstrated that motor dysfunction early in AD seems to predict cognitive and functional decline, institutionalization, and mortality. Thus, a preclinical screening model based on a functional assay composed of human cells to evaluate the effects of amyloidopathy and tauopathy in the motor and sensory segments of the peripheral nervous system (PNS) enables a platform for understanding multiplicative effects in AD and potentially identify biomarkers that could identify high risk AD patients at the preclincial stage, thus improving their clinical outcomes. We seek to use UCF’s functional systems to investigate AD in terms of deficits in sensory and motor function in collaboration with Dr. Morgan at MSU to complement our CNS AD functional models in response to the NOSI: Sensory and Motor System Changes as Predictors of Preclinical Alzheimer’s Disease (NOT-AG-20-053). Recently, Hickman published a model of the neuromuscular junction (NMJ) composed of human motoneurons (MNs) and human primary skeletal muscle (SkM) myotubes cultured in a serum-free medium for applications to ALS using iPSC derived mutant MNs. The system, with two chambers linked by microtunnels, supports axonal outgrowth to the muscle chamber and facilitated MN-stimulated SkM contraction as well as direct stimulation-induced SkM contraction. We also have established a functional sensory neuronal system where intrafusal fibers can be innervated by sensory neurons, stretched and the AP generation monitored at the neuronal cell body that can be integrated with piezoelectric sensors and actuators. We propose establishing a PNS model for AD using Aβ42 and tau oligomer dosed healthy systems in addition to motor and sensory systems composed of AD mutant iPSC-derived NMJ systems as an extension of our recently published CNS AD model. We hypothesize our AD PNS systems will exhibit characteristic disease pathology as well as uncover distinct functional deficits useful in a preclinical diagnostic capacity. We will determine functional deficits induced by the oligomers as well as monitor biomarkers in the medium to identify which biomarkers could be used in a companion blood test. We have preliminary data that Aβ oligomers have a deleterious effect on MN and NMJ function. Development of in vitro models of the PNS without cortical neuron components could establish definitively the effects of AD in the PNS.

项目摘要 在中枢神经之外，很少有体外模型检查阿尔茨海默氏病（AD）病理 系统。几项研究表明缺乏适当的临床前阿尔茨海默氏病及相关的 痴呆症（ADRD）模型是成功开发AD/ADRD疗法的障碍之一。发动机 损伤是早期AD病理学的共同特征，运动功能与运动功能之间的联系 开发广告已越来越被认可。步态异常已在开始之前 痴呆多年。现在很明显，治疗窗口，因此临床试验必须转移 对于轻度认知障碍（MCI）或更好的MCI阶段有效，但是，很少有 任何预测在此疾病阶段将发展广告的诊断。研究表明 AD早期运动功能障碍似乎可以预测认知和功能下降，制度化和死亡率。 这是一个基于由人类细胞组成的功能测定的临床前筛选模型，以评估影响 周围神经系统（PNS）的运动和感觉段中的淀粉样病和tauopathy 启用一个平台来理解AD中的乘法效应，并可能识别可能 在临床前确定高风险AD患者，从而改善其临床结果。我们试图使用 UCF的功能系统可以根据感觉和运动功能的定义进行协作调查广告 与MSU的Morgan博士一起完成了我们的CNS AD功能模型，以应对Nosi：Sensory和 运动系统随着阿尔茨海默氏病的预测因子而变化（NOT-AG-20-053）。最近，希克曼 发布了由人体运动神经元（MN）和人类组成的神经肌肉连接（NMJ）的模型 一级骨骼肌（SKM）肌管在无血清的培养基中培养的，用于使用IPSC应用于ALS 派生的突变MNS。该系统带有两个由微核连接的腔室，支持轴突的生长到 肌肉室和支持MN刺激的SKM收缩以及直接刺激诱导的SKM 收缩。我们还建立了一个功能性感觉神经元系统，可以在其中插入纤维 受感官神经元支配，拉伸和AP的产生在神经元细胞体处监测，可以 与压电传感器和执行器集成。我们建议使用Aβ42建立AD的PNS模型 除了由AD突变体组成的电动机和感觉系统外 IPSC衍生的NMJ系统是我们最近发布的CNS AD模型的扩展。我们假设广告 PNS系统将表现出特征性的疾病病理学，并发现有用的独特功能性缺陷 临床前诊断能力。我们将确定低聚物引起的功能缺陷以及监测 培养基中的生物标志物可以确定哪些生物标志物可用于伴侣血液测试。我们有 Aβ低聚物对MN和NMJ功能具有有害作用的初步数据。体外发展 没有皮质神经元成分的PNS模型可以确定地建立AD在PNS中的影响。