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.

项目概要 美国大约有 540 万人患有阿尔茨海默氏病 (AD)，导致严重的健康问题 70-80 岁的 AD 患者认知能力下降，死亡率加倍（与类似的情况相结合）。 目前，美国医疗保健系统每年花费约 2770 亿美元。 随着人口老龄化，β-淀粉样蛋白 (Aβ) 斑块显着增加，这是长期健康的关键。 术语，AD 的有效治疗 2013 年，使用化学衍生的细菌产品 monophos- 磷酰脂质 A (MPLA) 是脂多糖 (LPS) 脂质 A 区域的无毒衍生物，可防止 在小鼠模型中出现类似 AD 的症状，证明了一种相对便宜且有效的治疗途径 通过弱 Toll 样受体 4 (TLR4) 激动作用预防 AD 然而，存在一些问题。 MPLA，最重要的是产品的结构异构性和不一致性。 设计并在活细菌菌株中表达 MPLA 样功能同系物（脂寡糖，LOS） 我们生产和纯化的产品更加均质，且生产和纯化成本低廉。 测试了结构工程 MPLA 类 LOS（减毒脂质 A 治疗，ALT），即保护 当每周低剂量注射时，可消除易患 AD 的小鼠模型的学习障碍。 AD 的潜在病理生理学可能很早就开始了（早在表现为痴呆之前），并且它是 尽管经过数十年的努力，人们对 AD 的了解仍知之甚少。 通过持续、强烈的模式识别刺激，导致大脑慢性炎症的结果—— PRR 的配体有很多；特别是 TLR4，它们包括经典的 LPS（也包括）。 LOS 和脂质 A)，还有一些非经典分子，包括 Aβ 肽，因此，TLR4 上的竞争。 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 TLR4 微弱激活的小胶质细胞被证明在以下方面具有增加的吞噬活性： 包括 Aβ 的清除，我们已经证明 ALT 可以预防类似 AD 的学习障碍。 此外，由于 ALT 是由 ALT 产生的，因此提案将解决其他早发 AD 小鼠模型的保护问题。 活菌株，我们将研究活菌株作为潜在益生菌疗法的用途，而不是作为益生菌疗法 每周注射提取的 LOS，旨在开发一种活细菌益生菌来预防 AD。 是一种廉价且可能非常有效的 AD 预防和治疗方法。