Preventing Alzheimer's Disease with Designer Lipids

用设计脂质预防阿尔茨海默病

• 批准号: 10301042
• 负责人: Alison J Scott
• 金额: $ 19.31万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301042
• 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; 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; Phagocytes; Phosphoric Monoester Hydrolases; Physiological; Polysaccharides; Population; Presenile Alzheimer Dementia; 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; aqueous; cognitive function; combinatorial chemistry; cost; design; effective therapy; inorganic phosphate; lipooligosaccharide; morphogens; mortality; mouse model; mutant; prevent; probiotic therapy; stem; structured lipid; 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.

项目总结 在美国，大约有540万人患有阿尔茨海默氏症(AD)，导致显著的 认知能力下降，70-80岁患者的死亡率翻一番。AD(结合SIMI- 痴呆症)目前每年花费美国医疗系统约2,770亿美元。这一成本预计将在- 随着人口老龄化，皱纹显著增加。预防和清除淀粉样β蛋白(Aβ)斑块是长效的关键 长期有效治疗阿尔茨海默病。2013年，对一种化学衍生细菌产品单磷酸盐的管理- 磷脂A是脂多糖A区的一种无毒的衍生物，可预防 在小鼠模型中出现AD样症状，证明了一种相对廉价和有效的治疗方法 通过弱Toll样受体4(TLR4)激动剂预防AD。但是，存在以下几个问题 最重要的是产品的结构异质性和不一致性。相比之下，我们 设计并在活菌中表达MPLA样功能同源物(LOS) 生产出更均一的产品，生产和提纯成本低廉。我们已经制作了和 测试了一种结构工程的MPLA样LOS(减毒脂A治疗，ALT)，即Protec- 在易患AD的小鼠模型中，当给予每周低剂量注射时，可有效防止学习障碍。 阿尔茨海默病的潜在病理生理学很可能很早就开始了(早在表现为痴呆症之前)，而且 尽管经过几十年的努力，人们对此仍然知之甚少。然而，有大量报告表明，AD是 通过持续、强烈的模式识别刺激，大脑中的慢性炎症的后果- 凝集素受体(PRR)。PRR的配体很多；特别是TLR4，它们包括规范的内毒素(也 LOS和类脂A)，但也有包括Aβ肽在内的几个非正则分子。因此，TLR4的竞争 可能通过取代更多的促炎激动剂来预防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被证明在- 包括Aβ的清关。我们已经证明，ALT可以防止AD样学习障碍，这一点 该提案将解决其他早发性AD小鼠模型的保护问题。此外，由于ALT是从 活菌株，我们将研究活菌株作为一种潜在的益生菌疗法的用途，而不是 每周注射提取的LOS。这项提议旨在开发一种活的细菌益生菌来预防阿尔茨海默病。这 是一种廉价且潜在的高度有效的AD预防和治疗方法。