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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

基本信息

批准号：
10448570
负责人：
James J Hickman
金额：
$ 76.46万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
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/10448570
关键词：
Afferent Neurons Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos 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 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 Lead Link Longitudinal Studies Measurement Modeling Monitor Motor Motor Neurons Muscle Muscle Contraction Muscle Fibers Mutation Nervous System Physiology Neuraxis Neuromuscular Junction Neurons 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 abeta oligomer animal data base biological systems biomarker discovery 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 sensorimotor system sensory system small molecule success tau Proteins tau aggregation tool

项目摘要

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.