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（申请人提供）：TLR 4拮抗剂作为体内APOE调节的神经炎症的治疗性治疗β-淀粉样肽（A β），特别是可溶性寡聚A β 42（oA β）的水平升高，被认为是阿尔茨海默病（AD）的近端原因。oAbeta可以诱导直接神经毒性，并且oAbeta和含有Abeta 42的不溶性斑块都可以通过从神经胶质释放促炎细胞因子来诱导间接神经毒性。此外，延长的促炎反应可能导致神经胶质细胞对Abeta的吞噬清除减少。Toll样受体4（TLR 4）是先天免疫的基础，由神经元和胶质细胞表达，由oAbeta激活，因此可能在AD的神经炎症特征中起重要作用。然而，在体外和体内的数据是相互矛盾的，是否抑制TLR 4是有益的或有害的AD发病机制。总体关注集中在TLR 4抑制是否会预防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。然而，目前还没有关于TLR 4拮抗剂作为神经炎症治疗策略的功效的数据。AD的主要遗传风险因素是载脂蛋白E（apoE）的APOE 4基因遗传，与APOE 3相比，单或双等位基因的风险增加约4倍和15倍。APOE 4可能通过涉及Abeta积累和神经炎症的机制增加AD风险，两者均受TLR 4拮抗作用调节。我们的初步数据表明，在体内和体外，与APOE 3相比，APOE 4增加了LPS诱导的神经炎症。在体外，oAbeta对细胞因子分泌的诱导作用更大， apoE 4比apoE 3更强，这是一种被TLR 4拮抗作用抑制的反应。然而，TLR 4抑制的体内作用在表达家族性AD突变的转基因小鼠模型（FAD-Tg）中是未知的。在本提案中，我们将利用新型TLR 4拮抗剂，并在体外（目标1）鉴定最有效的候选物，以进行体内测试（目标2）。由于AD患者中APOE 4的患病率增加，以及与APOE 3相比，其对治疗干预的不同反应，因此在也表达人APOE的FAD-Tg小鼠中测试治疗剂至关重要。我们开发了这种新的临床前模型，即新型EFAD-Tg小鼠，并证明与E3 FAD相比，E4 FAD小鼠具有更大的认知障碍，突触可塑性降低，神经炎症和Abeta病理学增加，重要的是可溶性oAbeta增加。因此，目的2将使用在预防（4-6个月）和治疗（6-7个月）两种模式中用TLR 4拮抗剂治疗的EFAD小鼠，并与TLR 4激动剂相比，来检验我们的假设，即TLR 4拮抗剂抑制A β介导的APOE调节的神经炎症。总体而言，这项首次研究将为Abeta诱导的神经炎症和APOE 4诱导的AD风险的新机制（TLR 4）提供证据。如果对CNS病症尚未受到足够关注的TLR 4抑制是有效的靶标，则在体外和EFAD小鼠中鉴定的药代动力学、药效学、靶标接合和功效读数将使未来的AD命中发现或命中-o-先导TLR 4药物发现项目成为可能。