Impact of phagocytosis on amyloid beta-induced pathology

吞噬作用对β淀粉样蛋白诱导的病理学的影响

• 批准号: 10724363
• 负责人: Sanja Arandjelovic
• 金额: $ 44.41万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724363
• 关键词: Abeta clearance; Ablation; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid beta-Protein; Apoptosis; Apoptotic; Behavior; Brain; Cell Death; Cell physiology; Cells; Central Nervous System; Chronic; Communities; Cytoskeleton; Data; Deterioration; Development; Disease; Eating; Environment; Exhibits; Failure; Gene Expression Profile; Genetic; Health; Homeostasis; Immune; Impaired cognition; Impairment; Infection; Inflammation; Inflammatory Arthritis; Injury to Kidney; Knowledge; Learning; Link; Lysosomes; Mediating; Microglia; Mus; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organism; Pathologic; Pathology; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phosphatidylserines; Play; Process; Research; Resolution; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tissues; abeta accumulation; in vivo; innovation; mouse model; myelination; neuroprotection; patient population; pharmacologic; receptor; response; synaptic pruning; therapeutically effective; therapy design; transcriptomics

IMPACT OF PHAGOCYTOSIS ON AMYLOID BETA-INDUCED PATHOLOGY Abstract Alzheimer's disease (AD) is a devastating neurodegenerative disease that impacts more than 6 million Americans and millions more Worldwide. Despite years of active research, our understanding of this disease is incomplete, and the patient population remains without effective therapeutic options. In AD, clearance of apoptotic neurons and amyloid-beta aggregates is reduced, as microglia become overloaded with chronically phagocytosed debris. The current dogma suggests that decreased clearance of apoptotic cells, also known as “efferocytosis”, inevitably leads to pathology. However, our preliminary data suggest that this concept warrants further testing. We show here that pharmacologic or genetic efferocytosis reduction (not complete ablation) can reduce inflammation in mouse models of inflammatory arthritis and kidney injury, suggesting unexpected benefits of reduced clearance in inflammation. In this proposal, we will test the hypothesis that reduced efferocytosis alleviates amyloid-beta induced pathology through enhanced debris processing/degradation (due to reduced load of phagocytes such as microglia). We will pursue the following aims: 1. Using mice with genetic decrease in efferocytosis due to the combined loss of four different efferocytosis receptors, we will test debris (apoptotic cells, amyloid-beta aggregates, myelin debris) clearance, processing, and response of microglia ex vivo. 2. By crossing these mice with the mouse model of amyloid-beta induced pathology and Alzheimer's disease (5xFAD mice), we will quantify multiple disease parameters, determine the numbers of apoptotic cells in the brain, and analyze the microglial response in the reduced clearance environment in vivo. Our proposal is innovative because we will challenge the dogma that reduced efferocytosis is universally detrimental. Our proposal is significant because these studies will provide new knowledge to the community about the contribution of efferocytosis to AD pathology and provide new avenues to therapy in AD.

吞噬作用对淀粉样β蛋白致病作用的影响 摘要 阿尔茨海默病是一种毁灭性的神经退行性疾病，影响着600多万人 美国人和全世界数以百万计的人。尽管进行了多年的积极研究，但我们对这种疾病的理解是 不完整，患者群体仍然没有有效的治疗选择。 在阿尔茨海默病中，当小胶质细胞变成 堆满了长期吞噬的碎片。目前的教条表明，减少对 凋亡细胞，也被称为“泡细胞增多症”，不可避免地会导致病理。然而，我们的初步数据 建议这一概念值得进一步测试。我们在这里展示了药理学的或遗传性的泡沫化 减少(不是完全消融)可以减少炎性关节炎和肾脏模型的炎症 损伤，表明减少炎症清除的意外好处。 在这项提案中，我们将检验这样的假设，即减少泡腾作用可以减轻淀粉样β蛋白的诱导。 通过增强碎片处理/降解(由于减少吞噬细胞的负载，如 小胶质细胞)。我们将致力于实现以下目标：1.利用基因缺失的小鼠 联合丢失四种不同的泡腾受体，我们将检测碎片(凋亡细胞，淀粉样β蛋白 聚集体、髓鞘碎片)体外清除、加工和反应小胶质细胞。2.通过杂交这些老鼠 利用淀粉样β蛋白诱导的病理和阿尔茨海默病的小鼠模型(5xFAD小鼠)，我们将量化 多项疾病参数，测定脑组织中的凋亡细胞数，并分析小胶质细胞 在体内清除减少的环境中的反应。 我们的建议是创新的，因为我们将挑战减少泡泡吞噬是普遍存在的教条 有害的。我们的建议意义重大，因为这些研究将为社会提供新的知识。 探讨吞噬作用在AD病理中的作用，为AD的治疗提供新的途径。