Reduced Alzheimer's disease progression and neutrophil adhesion via competition using neutrophil-derived or engineered nanoparticles

通过使用中性粒细胞衍生的或工程化的纳米颗粒竞争，减少阿尔茨海默病的进展和中性粒细胞粘附

• 批准号: 10799111
• 负责人: SHAOYI JIANG
• 金额: $ 44.46万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10799111
• 关键词: APP-PS1; Adhesions; Aftercare; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Antibodies; Artificial nanoparticles; Binding; Binding Sites; Biological Assay; Biological Process; Biology; Blood; Blood capillaries; Blood flow; Brain; Cell membrane; Cells; Cerebrovascular Circulation; Cerebrovascular system; Circulation; Clinical; Cognition; Cognitive; Competitive Binding; Congenic Mice; Data; Development; Disease; Disease Progression; Dose; Drug Targeting; Dyes; Encapsulated; Engineering; Episodic memory; Exhibits; Frequencies; Future; Generations; Glycolates; Half-Life; Hour; Human; Image; Immune system; Immunocompromised Host; Impaired cognition; Inflammation; Inflammatory; Label; Masks; Membrane; Membrane Proteins; Memory; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neuronal Dysfunction; Outcome; Patients; Peptides; Performance; Pharmaceutical Preparations; Property; Proteins; Recovery; Resistance; Short-Term Memory; Signal Transduction; Site; Testing; Therapeutic; Titrations; Translating; Translations; Variant; Vegf inhibition; Wild Type Mouse; Work; abeta accumulation; biomaterial compatibility; cell type; cerebral capillary; clinical translation; cognitive function; extracellular vesicles; follow-up; immune function; immunogenicity; improved; in vivo; intravital imaging; large scale production; mouse model; multiphoton imaging; multiphoton microscopy; nanocarrier; nanomaterials; nanoparticle; neutrophil; novel; novel strategies; novel therapeutic intervention; particle; preservation; prevent; spatial memory; targeted treatment; therapeutic candidate; therapy outcome; transmission process; two photon microscopy; vascular inflammation

PROJECT SUMMARY Many Alzheimer’s disease (AD) drugs under development target aggregated amyloid beta (Aβ) peptide, but this approach is controversial due to disappointing clinical outcomes. Thus, the need to develop new therapeutic strategies for AD persists. Blood flow in the brain of Alzheimer disease patients is substantially decreased as compared to age-matched healthy controls. Recently, intravital imaging with two-photon microscopy showed that blood flow in AD mouse models is reduced because neutrophils plug up capillaries resulting in a small, but impactful number of stalled capillaries. Removing these stalls by interfering with neutrophil adhesion improves blood flow in minutes and also improves performance on tasks involving short term or episodic memory within hours. Although this approach is promising because it targets blood flow and inflammation, key features of AD unaddressed by amyloid-targeting drugs, it is currently limited to experimental treatments with limited possibility for clinical translation. Existing experimental approaches interfere with a protein not found in humans, Ly6G, or would cause severe compromise of the immune system. This proposal aims to develop a novel strategy based on highly biocompatible neutrophil-derived extracellular vesicles or nanoparticles that specifically target and block neutrophil adhesion sites in the brain to reduce capillary stalls and the associated blood flow deficits. These novel agents are encapsulated in neutrophil membranes that preserve many of the neutrophil functions so possess the same targeting capacity as neutrophils. When injected systemically, these engineered particles compete with neutrophils for binding sites on the brain capillaries, acting to reduce neutrophil arrest. Importantly, the particles are only <1% of the size of neutrophils and do not cause capillary stalls. The proposed work will engineer and characterize a novel AD therapy with the following Specific Aims: 1) Investigate the targeting of naturally- derived neutrophil EVs (nEVs) that are generated from congenic mouse donors. This aim will follow up on preliminary data that suggests these nEVs bind to capillaries in AD, but not wild type controls, and appear to decrease capillary stall frequency while increasing cerebral blood flow. 2) Explore the therapeutic potential of nEVs. Previous experimental capillary stall reduction strategies resulted in rapid recovery of memory function, so it is expected that the novel nEVs would have a similar effect as assayed by working and spatial memory tests. 3) Engineer neutrophil membrane-coated nanoparticles (NMPs) with cargo- carrying capabilities. This aim will develop a second-generation engineered particle based on the same neutrophil-membrane encapsulation as nEVs that could be loaded with drugs. This would provide the ability to target therapies specifically to stall-prone capillaries in the brain. The proposed work combines expertise in nanomaterials, extracellular vesicle biology, neurodegeneration, and in vivo multiphoton imaging to develop a novel treatment for AD.

项目总结 许多阿尔茨海默病(AD)药物正在开发中，靶向聚集的淀粉样β蛋白(Aβ)肽，但 由于临床结果令人失望，这种方法存在争议。因此，有必要开发新的 阿尔茨海默病的治疗策略仍然存在。阿尔茨海默病患者大脑中的血流实质上是 与年龄匹配的健康对照组相比有所下降。最近，双光子活体成像 显微镜显示AD模型小鼠的血流量减少是因为中性粒细胞堵塞毛细血管 导致少量但有冲击力的毛细血管停滞。通过干扰来移除这些摊位 中性粒细胞黏附可以在几分钟内改善血液流动，还可以提高在以下任务中的表现 短时记忆或短时记忆在数小时内。尽管这种方法很有希望，因为它针对的是血液 血流和炎症，AD的关键特征，未被淀粉样靶向药物解决，目前仅限于 临床翻译可能性有限的实验性治疗。现有的实验方法 干扰一种在人类中没有发现的蛋白质Ly6G，否则会导致免疫功能严重受损 系统。这项提议旨在开发一种基于高度生物相容性的中性粒细胞来源的新策略 特异性靶向和阻断中性粒细胞黏附部位的细胞外小泡或纳米颗粒 以减少毛细血管停滞和相关的血液流动缺陷。这些新型药剂被封装在 在中性粒细胞膜中，保留了许多中性粒细胞的功能，因此具有相同的靶向性 中性粒细胞的能力。当系统注射时，这些工程粒子与中性粒细胞竞争。 用于大脑毛细血管上的结合部位，以减少中性粒细胞的滞留。重要的是，这些粒子 只有中性粒细胞大小的1%，不会引起毛细血管停滞。拟议的工作将设计和实施 描述一种新的AD治疗方法，具有以下特定目的：1)研究天然靶向- 来自同基因小鼠捐赠者的衍生中性粒细胞EV(NEVS)。这一目标将跟进 初步数据表明，这些NEV与AD的毛细血管结合，但不是野生型对照，并出现 在增加脑血流量的同时减少毛细血管失速的频率。2)探索治疗方法 新能源汽车的潜力。以前的实验毛细失速减少策略导致快速恢复 记忆功能，因此预计新的NEVS将具有与工作测试类似的效果 和空间记忆测试。3)工程中性粒细胞膜包覆纳米颗粒(NMPs)与货物- 承载能力。该目标将在相同的基础上开发第二代工程粒子 中性粒细胞膜包裹为可载药的NEV。这将提供一种能力 专门针对大脑中易失速的毛细血管进行治疗。拟议的工作结合了专业知识 在纳米材料、细胞外囊泡生物学、神经退化和体内多光子成像中 开发治疗阿尔茨海默病的新方法。