Targeting TFEB To Microglia and Monocytes to Enhance Amyloid Degradation

将 TFEB 靶向小胶质细胞和单核细胞以增强淀粉样蛋白降解

• 批准号: 10191054
• 负责人: Abhinav Diwan
• 金额: $ 46.07万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191054
• 关键词: APP-PS1; Address; Adult; Affect; Age-Months; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Astrocytes; Attenuated; Behavioral; Biogenesis; Blood - brain barrier anatomy; Brain; Bromodeoxyuridine; Cell division; Cell physiology; Cells; Characteristics; Chromosome Mapping; Clinical; Cognitive deficits; DNA cassette; Data; Degradation Pathway; Dementia; Deposition; Effector Cell; Evaluation; Event; Genetic; Grant; Growth; Hematopoietic; Home; ITGAM gene; Immune; Impairment; Inflammation; Intercellular Fluid; Label; LoxP-flanked allele; Lysosomes; Metabolism; Microdialysis; Microglia; Mus; Myelogenous; Nerve Degeneration; Neuronal Dysfunction; Neurons; Outcome; Parabiosis; Pathogenesis; Pathologic; Pathology; Peptides; Peripheral; Peritoneal Macrophages; Phagocytes; Phagocytosis; Pharmacology; Physiological; Population; Preventive; Reporting; Residual state; Role; Senile Plaques; Source; Tamoxifen; Testing; Therapeutic; abeta accumulation; activating transcription factor; age related; aged; amyloid pathology; base; brain cell; brain parenchyma; cell type; gene therapy; improved; in vivo; interstitial; monocyte; mouse model; neurofibrillary tangle formation; overexpression; promoter; recruit; response; selective expression; self-renewal; transcription factor; uptake

PROJECT SUMMARY / ABSTRACT The pathogenesis of Alzheimer’s disease (AD), the most common cause of dementia, is characterized by the accumulation of Aβ in the interstitial fluid (ISF) and its aggregation into soluble oligomers and insoluble amyloid plaques. This triggers a cascade of events including the formation of neurofibrillary tangles, neuronal dysfunction and degeneration, ultimately resulting in clinical dementia. In sporadic AD, age-dependent compromise of lysosome function in various brain cell types has been implicated in impaired Aβ metabolism, resulting in accelerated pathogenesis. Microglia, the primary immune cell in the brain phagocytose Aβ and amyloid plaques; but are observed to be engorged with residual amyloid material, suggesting impairment of lysosomal degradative capacity. Microglia are an isolated self-renewing population within the brain and peripheral monocytes do not cross the blood brain barrier under normal physiological conditions. Whether monocytes enter the AD brain is a current source of controversy. Our preliminary data with a fate-mapping strategy demonstrate that peripheral monocytes home in to amyloid plaques in aged APP/PS1 mice, a model of AD pathogenesis and take up amyloid material. Peripheral monocytes are more amenable to targeting via gene therapy or pharmacologic approaches than resident microglia and thus offer an opportunity to stimulate lysosomal function in cells that will target plaques within the brain parenchyma. We have demonstrated that exogenous expression of transcription factor EB (TFEB), a master inducer of lysosomal degradative pathways, stimulates lysosome biogenesis and function in astrocytes, to upregulate Aβ uptake via macropinocytosis and accelerate its lysosomal degradation resulting in attenuated amyloid plaques. Whether targeting TFEB to resident microglia or circulating monocytes facilitates amyloid phagocytosis and lysosomal degradation to attenuate plaque pathogenesis and improve neuronal function, needs to be explored. Hypothesis: Ontogeny-based targeting of exogenous TFEB to microglia and peripheral monocytes is sufficient to stimulate amyloid uptake and degradation; and attenuate amyloid plaques and neuronal pathology in AD. To test this hypothesis, we propose three specific aims: SA1: Determine if enhancing lysosomal function with TFEB expression in microglia attenuates plaque pathogenesis in AD mouse models. SA2: Examine the role of peripheral monocyte recruitment in amyloid plaque pathogenesis. SA3: Determine if enhancing TFEB expression specifically in circulating monocytes affects monocyte recruitment and plaque pathogenesis in AD mouse models.

项目摘要/摘要 阿尔茨海默病（AD）是痴呆的最常见原因，其发病机制的特征在于： Aβ在间质液（ISF）中的蓄积及其聚集成可溶性寡聚体和不溶性寡聚体 淀粉样斑块这引发了一系列事件，包括神经元缠结的形成，神经元 功能障碍和退化，最终导致临床痴呆。在散发性AD中， 各种脑细胞类型中溶酶体功能的损害与受损的Aβ代谢有关， 导致加速发病。小胶质细胞是脑内吞噬Aβ的主要免疫细胞， 淀粉样斑块;但观察到充满残留的淀粉样物质，表明 溶酶体降解能力。小胶质细胞是大脑中孤立的自我更新群体， 在正常生理条件下，外周单核细胞不能穿过血脑屏障。是否 单核细胞进入AD脑是目前争议的来源。我们的初步数据与命运映射 策略表明外周单核细胞会回到老年APP/PS1小鼠（一种模型）的淀粉样蛋白斑块中 AD的发病机制和淀粉样物质的摄取。外周血单核细胞更容易通过基因靶向 治疗或药理学方法比居民小胶质细胞，从而提供了机会，刺激 细胞中的溶酶体功能将靶向脑实质内的斑块。我们已经证明 转录因子EB（TFEB）的外源性表达，TFEB是溶酶体降解途径的主要诱导物， 刺激星形胶质细胞中的溶酶体生物发生和功能，通过巨胞饮作用上调Aβ摄取， 加速其溶酶体降解，从而导致淀粉样蛋白斑变弱。是否针对TFEB， 驻留的小胶质细胞或循环单核细胞促进淀粉样蛋白吞噬作用和溶酶体降解， 减轻斑块发病机制和改善神经功能，需要探索。 假设：基于个体发生的外源性TFEB靶向小胶质细胞和外周单核细胞是足够的 刺激淀粉样蛋白摄取和降解;并减弱AD中的淀粉样蛋白斑块和神经元病理。 为了验证这一假设，我们提出了三个具体的目标：SA 1：确定是否增强溶酶体功能， 小胶质细胞中TFEB表达减弱AD小鼠模型中斑块发病机制SA 2：检查 淀粉样斑块发病机制中的外周单核细胞募集。SA 3：确定增强TFEB表达是否 特异性地影响AD小鼠单核细胞募集和斑块发病机制 模型