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.

项目概要 很少有体外模型可以检查中枢神经以外的阿尔茨海默病 (AD) 病理学 系统。多项研究表明，缺乏适当的临床前阿尔茨海默病及相关疾病的治疗方法。 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 病理学的一个共同特征，运动功能与 AD 风险之间存在联系 发展 AD 已越来越受到人们的认可。已发现步态异常先于 痴呆多年。现在越来越明显的是，治疗窗口和临床试验必须改变 对于轻度认知障碍 (MCI) 或更好的是 MCI 前阶段有效，但是，如果 任何预测谁会在疾病的这个阶段患上 AD 的诊断。研究表明 AD 早期的运动功能障碍似乎预示着认知和功能下降、住院治疗和死亡率。 因此，基于由人体细胞组成的功能测定的临床前筛选模型来评估效果 周围神经系统 (PNS) 运动和感觉节段的淀粉样变性和 tau 蛋白变性 提供了一个了解 AD 乘数效应的平台，并有可能识别出可以 在临床前阶段识别高风险 AD 患者，从而改善他们的临床结果。我们寻求使用 UCF 的功能系统合作研究 AD 的感觉和运动功能缺陷 与 MSU 的 Morgan 博士合作，补充我们的 CNS AD 功能模型，以响应 NOSI：感觉和 运动系统变化作为临床前阿尔茨海默病的预测因素 (NOT-AG-20-053)。最近，希克曼 发表了由人类运动神经元（MN）和人类组成的神经肌肉接头（NMJ）模型 在无血清培养基中培养的原代骨骼肌 (SkM) 肌管，用于使用 iPSC 应用于 ALS 衍生的突变 MN。该系统有两个通过微通道连接的室，支持轴突的生长 肌室并促进 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系统，其中梭内纤维可以 由感觉神经元支配，拉伸并在神经元细胞体上监测 AP 的生成，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 AD 突变体组成的运动和感觉系统外，还给健康系统注射了 tau 寡聚体 iPSC 衍生的 NMJ 系统作为我们最近发布的 CNS AD 模型的扩展。我们假设我们的AD PNS 系统将表现出特征性的疾病病理学，并揭示独特的功能缺陷，有助于 临床前诊断能力。我们将确定寡聚物引起的功能缺陷并监测 培养基中的生物标志物，以确定哪些生物标志物可用于伴随血液测试。我们有 初步数据表明 Aβ 寡聚体对 MN 和 NMJ 功能具有有害影响。体外开发 没有皮质神经元成分的 PNS 模型可以明确地确定 AD 对 PNS 的影响。