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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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 /摘要阿尔茨海默氏病（AD）的发病机理是痴呆症的最常见原因，其特征是 Aβ在间质流体（ISF）中的积累及其聚集成固体寡聚物和不溶性淀粉样斑块。这触发了一系列事件，包括形成神经原纤维缠结，神经元功能障碍和变性，最终导致临床痴呆。在零星的广告中，依赖年龄在Aβ代谢受损中，各种脑细胞类型中溶酶体功能的妥协已被浸渍导致加速发病机理。小胶质细胞，脑吞噬Aβ和淀粉样斑；但观察到与残留的淀粉样蛋白材料互动，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人群，在正常生理条件下，周围单核细胞不会越过血脑屏障。无论单核细胞进入AD大脑是当前争议的来源。我们的初步数据和命运映射策略表明，外围单核细胞在老年App/PS1小鼠的淀粉样蛋白斑中居住，这是一种模型 AD发病机理并吸收淀粉样蛋白材料。外围单核细胞更适合通过基因靶向治疗或药物方法比居民小胶质细胞，因此提供了刺激的机会细胞中的溶酶体功能将靶向脑实质内的斑块。我们已经证明了转录因子EB（TFEB）的外源表达，溶酶体降解途径的主要诱导剂，刺激星形胶质细胞中的溶酶体生物发生和功能，以通过大型细胞增多症上调Aβ的摄取和加速其溶酶体降解，导致淀粉样斑块减弱。是否针对TFEB 居民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至需要探索衰减斑块发病机理并改善神经元功能。假设：外源TFEB对小胶质细胞和周围单核细胞的基于个体的靶向就足够了刺激淀粉样蛋白的摄取和降解；并减弱AD中的淀粉样蛋白斑块和神经元病理。为了检验这一假设，我们提出了三个具体目标：SA1：确定是否增强了溶酶体功能小胶质细胞中的TFEB表达可减弱AD小鼠模型中的斑块发病机理。 SA2：检查淀粉样菌斑发病机理中的外周单核细胞募集。 SA3：确定是否增强TFEB表达特别是在循环单核细胞中影响AD小鼠的单核细胞募集和斑块发病机理型号。