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.

项目摘要 许多阿尔茨海默氏病（AD）在发育中的药物（AD）靶标的淀粉样蛋白β（Aβ）肽，但 由于令人失望的临床结果，这种方法引起了争议。那，需要开发新的 广告的治疗策略持续存在。阿尔茨海默氏病患者大脑中的血液流量基本上是 与年龄匹配的健康对照相比，下降量下降。最近，用两光子的静脉成像 显微镜表明，AD小鼠模型中的血流减少了，因为中性粒细胞插入毛细血管 导致了少量但有影响力的毛细血管。通过干扰这些摊位 中性粒细胞粘合剂可在几分钟内改善血液流动，并改善涉及任务的性能 几小时内短期或情节记忆。尽管这种方法很有希望，因为它针对血液 流量和注射，AD的关键特征未经淀粉样蛋白靶向药物，目前仅限于 实验治疗可能有限的临床翻译。现有的实验方法 干扰人类未发现的蛋白 系统。该建议旨在制定基于高度生物相容性中性粒细胞衍生的新型策略 细胞外蔬菜或纳米颗粒，这些蔬菜或纳米颗粒专门针对和阻塞中性粒细胞粘附部位 大脑减少毛细管摊位，相关的血流定义。这些新颖的代理被封装 在保留许多中性粒细胞功能的中性粒细胞膜中，具有相同的靶向 作为中性粒细胞的能力。当全身注射时，这些工程的颗粒与中性粒细胞竞争 对于脑毛细血管上的结合位点，采取行动减少中性粒细胞的停滞。重要的是，粒子是 仅<1％的嗜中性粒细胞，不会引起毛细血管失速。拟议的工作将设计和 以以下特定目的表征新的广告疗法：1）研究自然的靶向 衍生的嗜中性粒细胞EV（NEV）是由优先小鼠供体产生的。这个目标将跟进 提示这些NEV与AD中的毛细血管结合的初步数据，而不是野生型控制，并且出现 降低毛细管失速频率，同时增加脑血流。 2）探索治疗性 NEV的潜力。先前的实验毛细管减少策略导致 内存功能，因此可以预期，新颖的NEV会产生与工作相似的效果 和空间记忆测试。 3）工程师中性粒细胞膜涂层的纳米颗粒（NMP） 携带能力。这个目标将基于相同的第二代工程粒子发展 中性粒细胞膜的包裹为可以加载药物的NEV。这将提供能力 针对专门针对大脑中的易位毛细血管的疗法。拟议的工作结合了专业知识 在纳米材料中，细胞外囊泡生物学，神经变性和体内多光子成像 为AD开发新的治疗方法。