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症（AD），造成显着的 认知能力下降，70-80岁患者的死亡率增加一倍。AD（与simi- 目前，美国医疗保健系统每年花费约2770亿美元。预计成本将在- 随着人口的老龄化，预防和清除β淀粉样蛋白（Aβ）斑块是长期- 有效治疗AD。在2013年，施用化学衍生的细菌产品， 甲酰基脂质A（MPLA），一种脂多糖（LPS）脂质A区的无毒衍生物，阻止了 在小鼠模型中AD样症状的发作，证明了一种相对便宜和有效的途径， 通过弱Toll样受体4（TLR 4）激动预防AD。然而，有几个问题， MPLA，最重要的是产品的结构异质性和不一致性。相反，我们 设计并在活细菌菌株中表达MPLA样功能同系物（脂寡糖，LOS） 其产生更均匀产物且生产和纯化便宜。我们生产和 测试了一种结构工程化的MPLA样LOS（减毒脂质A治疗剂，ALT），它是保护性的， 在AD易感小鼠模型中，当每周低剂量注射时， AD的潜在病理生理学可能很早就开始（早在表现为痴呆之前）， 尽管经过了几十年的努力，人们仍然对它知之甚少。然而，有许多报告表明，AD是 大脑中慢性炎症的结果，通过持续的，强烈的模式识别刺激， 离子受体（PRR）。PRR的配体有很多;特别是对于TLR 4，它们包括典型的LPS（也 LOS和脂质A），但也包括几种非典型分子，包括Aβ肽。因此，TLR 4的竞争 可以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TLR 4弱活化的小胶质细胞显示出在- 包括Aβ的清除率。我们已经证明，ALT可以防止AD样学习障碍， 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是由 活菌株，我们将研究使用活菌株作为潜在的益生菌疗法，而不是作为一种治疗方法。 每周注射提取的LOS。该提案旨在开发一种活的细菌益生菌来预防AD。这 是预防和治疗AD的一种廉价且具有潜在高度影响力的方法。