TLR4 antagonists as a therapeutic treatment for APOE-modulated neuroinflammation

TLR4 拮抗剂作为 APOE 调节的神经炎症的治疗方法

• 批准号: 8769044
• 负责人: MARY JO LADU
• 金额: $ 19.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769044
• 关键词: Acute; Address; Aftercare; Aging; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Attention; Behavior; Brain; Caring; Characteristics; Chronic; Clinical Trials; Collaborations; Conflict (Psychology); Data; Dementia; Deposition; Drug Kinetics; Elderly; Epidemic; Epidemiologic Studies; Future; Genes; Genetic; Genetic Polymorphism; Health; Human; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Inhibitory Concentration 50; Institutes; Lead; Letters; Ligands; Lipid A; Measures; Mediating; Microglia; Mus; Mutation; Natural Immunity; Neuroglia; Neurons; Non-Steroidal Anti-Inflammatory Agents; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacodynamics; Plasma; Pre-Clinical Model; Prevalence; Prevention; Prevention strategy; Process; Proteins; Reading; Risk; Role; Senile Plaques; Signal Transduction; Slice; Staging; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Tumor Necrosis Factor-alpha; United States; abeta accumulation; amyloid induced neuroinflammation; amyloid peptide; apolipoprotein E-3; apolipoprotein E-4; beta amyloid pathology; cost; cytokine; drug discovery; extracellular; familial Alzheimer disease; genetic risk factor; improved; in vivo; mouse model; mutant; neuroinflammation; neurotoxic; neurotoxicity; novel; prevent; programs; response; therapeutic target; toll-like receptor 4

DESCRIPTION (provided by applicant): TLR4 antagonists as a therapeutic treatment for APOE-modulated neuroinflammation in vivo Increased levels of the peptide amyloid beta (Abeta), particularly as soluble oligomeric Abeta42 (oAbeta), are considered the proximal cause of Alzheimer Disease (AD). oAbeta can induce direct neurotoxicity, and both oAbeta and insoluble plaques containing Abeta42 can induce indirect neurotoxicity via pro-inflammatory cytokine release from glia. In addition, a prolonged pro-inflammatory response may result in decreased phagocytic clearance of Abeta by glia. Toll like receptor 4 (TLR4) is fundamental for innate immunity, is expressed by neurons and glia, is activated by oAbeta, and therefore may a significant role in the neuroinflammation characteristic of AD. However, in vitro and in vivo data are conflicting as to whether inhibiting TLR4 is beneficial or detrimental for AD pathogenesis. Overall concern centers on whether TLR4 inhibition will prevent Aβ-induced neuroinflammation and reduce Abeta levels or increase Abeta levels and neuroinflammation. However, there currently are no data on the efficacy of TLR4 antagonists as a therapeutic strategy for neuroinflammation. The primary genetic risk factor for AD is inheritance of the APOE4 gene for apolipoprotein E (apoE), increasing the risk approximately 4- and 15-fold with a single or double allele, compared to APOE3. APOE4 may increase AD risk through mechanisms involving Abeta accumulation and neuroinflammation, both modulated by TLR4 antagonism. Our preliminary data demonstrate that LPS-induced neuroinflammation is increased with APOE4 compared to APOE3 in vivo and in vitro. In vitro, the induction of cytokine secretion by oAbeta is greater with apoE4 than apoE3, a response inhibited by TLR4-antagonism. However, the in vivo effects of TLR4 inhibition are unknown in a transgenic mouse model expressing familial AD mutations (FAD-Tg). In this proposal we will utilize novel TLR4 antagonists and identify the most efficacious candidate in vitro (Aim 1) to test in vivo (Aim 2). Because of the increased prevalence of APOE4 in AD patients and their differential response to therapeutic interventions compared to APOE3, it is critical to test therapeutics in FAD-Tg mice that also expresses human APOE. We have developed this new preclinical model, the novel EFAD-Tg mice, and demonstrate that compared to E3FAD, E4FAD mice have a greater cognitive impairment, decreased synaptic plasticity, and increased neuroinflammation and Abeta pathology, importantly, an increase in soluble oAbeta. Therefore, Aim 2 will test our hypothesis that TLR4 antagonists inhibit Abeta-meditated APOE-modulated neuroinflammation using EFAD mice treated with a TLR4 antagonist in both prevention (4-6 months) and treatment (6-7 months) paradigms, and compared to a TLR4 agonist. Overall this first study, will provide evidence for a novel mechanism (TLR4) underlying both Abeta-induced neuroinflammation and APOE4-induced AD risk. If TLR4 inhibition, which has not received sufficient attention for CNS conditions, is a valid target, the pharmacokinetic, pharmacodynamic, target engagement and efficacy read-outs identified both in vitro and in EFAD mice will enable future hit-finding or hit-o-lead TLR4 drug discovery projects for AD.

描述（由适用提供）：TLR4拮抗剂是一种治疗治疗的治疗方法，用于apoE调节的体内神经炎症增加，肽淀粉样β（ABETA）的水平增加了，尤其是作为可溶性寡聚Abeta42（oabeta），被认为是Alzheimer病（AD）的近代原因。 Oabeta可以诱导直接的神经毒性，并且含有Abeta42的Oabeta和不溶性斑块都可以通过胶质细胞促进性细胞因子释放诱导间接神经毒性。此外，长时间的促炎反应可能导致神经胶质对Abeta的吞噬清除率降低。像受体4（TLR4）的收费是先天免疫的基础，由神经元和神经胶质表达，被Oabeta激活，因此在AD的神经炎症特征中可能起重要作用。然而，在体外和体内数据上，抑制TLR4是否对AD发病机理有益或有害。总体上关注的是TLR4抑制是否会防止Aβ诱导的神经炎症并降低ABETA水平或增加ABETA水平和神经炎症。但是，目前尚无关于TLR4拮抗剂作为神经炎症的治疗策略的效率的数据。与APOE3相比，AD的主要遗传危险因素是载脂蛋白E（APOE）的APOE4基因（APOE）的遗传，用单个或双等位基因增加了大约4倍和15倍的风险。 APOE4可以通过涉及Abeta积累和神经炎症的机制来增加AD风险，均由TLR4拮抗作用调节。我们的初步数据表明，与体内和体外的APOE3相比，APOE4与APOE4相比，LPS诱导的神经炎症增加。在体外，oabeta诱导细胞因子分泌更大，随着 APOE4比APOE3，这是TLR4-抗抗变性抑制的响应。但是，在表达家庭AD突变（FAD-TG）的转基因小鼠模型中，TLR4抑制的体内效应尚不清楚。在此提案中，我们将利用新型的TLR4拮抗剂，并在体外确定最有效的候选者（AIM 1）在体内测试（AIM 2）。由于AD患者的APOE4患病率增加，并且与APOE3相比，它们对治疗干预措施的反应不同，对于也表达人APOE的FAD-TG小鼠测试治疗至关重要。我们已经开发了这种新的临床前模型，即新型的EFAD-TG小鼠，并证明与E3FAD相比，E4FAD小鼠具有更大的认知障碍，突触可塑性降低，神经炎症和ABETA病理学的增加，重要的是，固体OABETA的增加。因此，AIM 2将检验我们的假设，即TLR4拮抗剂使用用TLR4拮抗剂在预防（4-6个月）和治疗（6-7个月）范式中使用TLR4拮抗剂治疗的EFAD小鼠抑制APOE调节的神经炎症，并与TLR4 Agonist进行了比较。总体而言，第一项研究将为ABETA诱导的神经炎症和APOE4诱导的AD风险提供新的机制（TLR4）提供证据。如果尚未受到CNS条件的兼容关注的TLR4抑制作用是有效的目标，那么在体外和Efad小鼠中确定的药代动力学，药效学，目标参与和有效性读数将启用未来的命中率调查或HIT-O-LEAD-O-LEAD-LEAD TLR4 TLR4药物发现项目。