Investigation of the role of glia cells in Alzheimers pathogenesis in a functional human-based in vitro model

在功能性人体体外模型中研究神经胶质细胞在阿尔茨海默病发病机制中的作用

• 批准号: 10323685
• 负责人: Xiufang Guo
• 金额: $ 14.82万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323685
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Anti-Inflammatory Agents; Astrocytes; Autologous; Bioinformatics; Biological Assay; Biological Markers; Brain; Cells; Central Nervous System Diseases; Chronology; Clinical; Cognitive deficits; Data; Data Analyses; Data Collection; Dementia; Deterioration; Development; Diagnostic; Disease; Disease Progression; Elderly; Electrophysiology (science); Etiology; Event; Foundations; Funding; Future; Genes; Genetic; Goals; Human; Hybrids; Immune; Immune system; Impaired cognition; In Vitro; Inflammation; Intervention; Investigation; Laboratories; Long-Term Potentiation; Maintenance; Memory; Microglia; Modeling; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neurosciences; Onset of illness; Outcomes Research; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Patients; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Play; Prevalence; Preventive therapy; Publications; Risk; Role; Solid; Source; Surface; Symptoms; Synapses; System; Systems Analysis; Technology; United States; age related; base; care costs; cognitive function; diagnostic biomarker; drug testing; effective therapy; experience; familial Alzheimer disease; functional disability; glial activation; human model; human old age (65+); human very old age (85+); immune activation; improved; in vitro Model; induced pluripotent stem cell; longitudinal analysis; loved ones; mutant; neural circuit; neural model; neuroinflammation; new therapeutic target; novel; organ on a chip; patch clamp; pre-clinical; response; stem cell differentiation; stem cells; synaptogenesis; tau Proteins; therapeutic development; therapeutic target; therapeutically effective; β-amyloid burden

Scientific Abstract / Summary Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder characterized by progressive cognitive decline that leads to age-related dementia. The five approved medications provide only modest symptomatic benefits and provide little effect in halting the disease progression. Improving the mechanistic understanding of disease onset and progression is essential for developing effective AD drugs. Decades of effort have focused on “neuron-centric” mechanisms by targeting amyloid beta (Aβ) and Tau pathologies. Recently neuroinflammation has gained increasing recognition as being an active component in AD etiology. It is becoming crucial to decipher the activation mechanism of astrocytes and microglia, the major players in CNS neuroinflammation, and their interactions with neurons during AD pathology. However, the mechanisms of glial activation and their interplay with neurons is poorly understood, especially in humans, due to the lack of proper models. This study endeavors to develop a human-based functional system that enables the mechanistic study concerning neuron-glia interactions, by taking the advantage of the progress made in induced pluripotent stem cell (iPSC) and Bio-MEMs (microelectromechanical systems) technology. The Specific Aims are: 1) Investigate the functional deficits of cortical neurons derived from AD patients on patterned MEAs, by quantifying the amplitude and maintenance of induced long term potentiation (LTP) and the number of functional synapses, compared to cortical neurons derived from healthy subjects. The longitudinal progression of the phenotype will also be analyzed. Integration of AD-cortical neurons expressing a familial AD gene could uncover the autologous functional phenotype in these neurons. 2) Develop a human-based tri-culture model consisting of human iPSC-derived cortical neurons, astrocytes and microglia, to investigate the neuron- glia interaction in AD. Both the effect of glial cells on the functionality of AD-neurons and the activation status of glia in the tri-culture will be examined. The results will help clarify whether astrocytes and microglia are still protective in the presence of AD-neurons, or becoming toxic at a certain point during the pathological process. The iPSC-sourced feature enables the possibility of patient-specific modeling. The non-invasive MEA system allows chronological monitoring of neural circuit function which is critical to investigate aging-related diseases. Functional readouts, long-term potentiation (LTP) and synapse number have been shown to imitate some clinical cognitive deficits. The model provides an ideal platform for investigating the early pathology and progression of functional impairment of AD-neurons and their interactions with glia. Application of this model could uncover essential mechanisms of glial activation, their interaction with neurons, and reveal potential therapeutic targets for AD. Both the platform and the etiological discoveries could accelerate the development of effective treatments for AD.

科学摘要/摘要