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蛋白诱导的病理学的影响 摘要 阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，影响超过600万人 美国人和全世界数百万人。尽管经过多年的积极研究，我们对这种疾病的理解是 不完全，患者群体仍然没有有效的治疗选择。 在AD中，凋亡神经元和淀粉样蛋白-β聚集体的清除减少，因为小胶质细胞变得 长期被吞噬的碎片超载目前的教条表明， 凋亡细胞，也称为“细胞增生症”，不可避免地导致病理学。然而，我们的初步数据显示， 这表明这个概念值得进一步测试。我们在这里表明，药理学或遗传性红细胞增多症， 减少（不完全消融）可以减少炎症性关节炎和肾脏的小鼠模型中的炎症 损伤，表明炎症中清除率降低的意想不到的益处。 在这个提议中，我们将检验减少的β-淀粉样蛋白增多症使β-淀粉样蛋白诱导的 通过增强的碎片处理/降解（由于减少的吞噬细胞负荷， 小胶质细胞）。我们将追求以下目标：1。使用由于遗传性白细胞增多症而遗传性减少的小鼠， 结合四种不同的细胞凋亡受体的损失，我们将测试碎片（凋亡细胞，β淀粉样蛋白 聚集体、髓磷脂碎片）的清除、加工和离体小胶质细胞的反应。2.通过让这些老鼠杂交 利用β淀粉样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 多个疾病参数，确定脑中凋亡细胞的数量，并分析小胶质细胞 在体内清除率降低的环境中的反应。 我们的建议是创新的，因为我们将挑战减少红细胞增多症是普遍存在的教条。 有害的我们的建议很重要，因为这些研究会为社会提供新的知识 关于红细胞增多症对AD病理学的贡献，并为AD的治疗提供新的途径。