Preventing Alzheimer's Disease with Designer Lipids

用设计脂质预防阿尔茨海默病

• 批准号: 10475150
• 负责人: Alison J Scott
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475150
• 关键词: APP-PS1; Abeta clearance; Address; Adjuvant; Age; Agonist; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid beta-Protein; Amyloid deposition; Antibiotics; Attenuated; Binding; Biochemical; Blood; Brain; Cause of Death; Chemicals; Chronic; Cognitive; Complex; Dementia; Development; Disease; Dose; Early Onset Alzheimer Disease; Endotoxins; Engineered Probiotics; Engineering; Enteral; Escherichia coli; FDA approved; Francisella; Functional disorder; Generations; Genes; Genome; Healthcare Systems; Heterogeneity; Homologous Gene; Hydrolysis; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injections; Intervention; Investigation; Lead; Learning; Ligands; Link; Lipid A; Lipids; Lipopolysaccharides; Microglia; Modification; Mus; Myelogenous; Oral; Parents; Pathologic; Pathology; Patients; Pattern recognition receptor; Peptides; Persons; Phagocytes; Phosphoric Monoester Hydrolases; Physiological; Polysaccharides; Population; Prevention; Prevention therapy; Probiotics; Process; Property; Protocols documentation; Reporting; Route; Salmonella enterica; Senile Plaques; Severities; Solubility; Structure; Symptoms; TLR4 gene; Testing; Therapeutic; Tissues; Transgenic Mice; Vent; Work; aged; antagonist; aqueous; cognitive function; combinatorial chemistry; cost; design; effective therapy; inorganic phosphate; lipooligosaccharide; morphogens; mortality; mouse model; mutant; prevent; probiotic therapy; rational design; stem; sugar; systemic inflammatory response

PROJECT SUMMARY Approximately 5.4 million people in the USA are afflicted with Alzheimer's Disease (AD), causing a marked cognitive decline and a doubling of the mortality rate for afflicted patients aged 70-80. AD (combined with simi- lar dementias) currently costs the USA healthcare system ~$277 billion a year. That cost is predicted to in- crease significantly as the population ages. Preventing and clearing amyloid beta (Aβ) plaque is key to long- term, effective treatment of AD. In 2013, administration of a chemically-derived bacterial product, monophos- phoryl lipid A (MPLA), a non-toxic derivative of the lipid A region of lipopolysaccharide (LPS), prevented the onset of AD-like symptoms in a mouse model, demonstrating a relatively inexpensive and effective route for AD prevention through weak Toll-like receptor 4 (TLR4) agonism. However, there are several problems with MPLA, the most important being the structural heterogeneity and inconsistency of the product. In contrast, we designed and expressed an MPLA-like functional homolog (lipooligosaccharide, LOS) in live bacterial strains that yield a more homogeneous product and are inexpensive to produce and purify. We have produced and tested a structurally-engineered MPLA-like LOS (Attenuated Lipid A Therapeutic, ALT), that is protec- tive from learning impairment in an AD-prone mouse model when given as a weekly low-dose injection. The underlying pathophysiology of AD likely starts very early (well before presentation as dementia) and it is still poorly understood, despite decades of effort. However, there are numerous reports suggesting that AD is the consequence of chronic inflammation in the brain, through persistent, strong stimulation of pattern recogni- tion receptors (PRR). Ligands for PRRs are numerous; specifically for TLR4 they include canonical LPS (also LOS and lipid A), but also several non-canonical molecules including Aβ peptide. Thus, competition at TLR4 may prevent inflammation associated with amyloid deposition by displacing more pro-inflammatory agonists. Further, microglial cells weakly activated through TLR4 were shown to have increased phagocytic activity in- cluding clearance of Aβ. We have demonstrated that ALT protects from AD-like learning impairment and this proposal will address protection in other early onset AD mouse models. Further, since ALT is produced from a live bacterial strain, we will investigate the use of the live strain as a potential probiotic therapy rather than a weekly injection of extracted LOS. This proposal aims to develop a live bacterial probiotic to prevent AD. This is an inexpensive and potentially highly impactful approach to AD prevention and therapy.

项目摘要 美国约有540万人患有阿尔茨海默氏病（AD），造成了明显的 认知能力下降和70-80岁患者的死亡率增加一倍。广告（与 LAR DEMENTIAS）目前每年损失美国医疗保健系统约2770亿美元。预计该费用将是 随着人口年龄的增长，折痕显着。预防和清除淀粉样β（Aβ）斑块是长期的关键 术语，有效的AD处理。 2013年，给药化学衍生的细菌产品，单声道 脂质脂质A（MPLA）是一种脂多糖A区（LPS）的无毒衍生物（LPS），阻止了该区域 小鼠模型中AD样症状的发作，证明了相对便宜且有效的途径 通过弱Toll样受体4（TLR4）激动剂预防AD。但是，有几个问题 MPLA，最重要的是产品的结构异质性和不一致。相反，我们 在活细菌菌株中设计并表达了MPLA样功能同源物（LOS） 这产生了更均匀的产品，并且生产和净化便宜。我们已经生产了 测试了一种结构设计的MPLA样LOS（脂质脂质a脂质A Alt），ALT） 在每周低剂量注射时给予AD易于的小鼠模型中的学习障碍。 AD的潜在病理生理可能很早就开始（良好作为痴呆症之前），这是 多斯蒂斯数十年来仍然很糟糕。但是，有许多报告表明广告是 大脑慢性炎症的结果，通过持续的强烈刺激模式识别 tion受体（PRR）。 PRR的配体很多；专门针对TLR4，它们包括规范LP（也包括 LOS和脂质A），但还包括包括Aβ肽在内的几种非典型分子。那是TLR4的竞争 通过取代更多的促炎激动剂，可以防止与淀粉样蛋白沉积相关的炎症。 此外，通过TLR4弱激活的小胶质细胞显示出吞噬活性增加的 - 包括清除Aβ。我们已经证明，ALT可以保护类似广告的学习障碍，这是 建议将解决其他早期AD鼠标模型中的保护。此外，由于Alt是由 活细菌菌株，我们将研究活菌株作为潜在益生菌疗法的使用，而不是 每周注射提取的LOS。该建议旨在开发一种活细菌益生菌以防止AD。 是一种廉价且潜在影响的预防和治疗方法。