A flavonoid gamma-secretase modulator (GSM) reduces beta-amyloid and tau pathologies in the AD mice

类黄酮 γ 分泌酶调节剂 (GSM) 可减少 AD 小鼠的 β-淀粉样蛋白和 tau 蛋白病理

• 批准号: 9127058
• 负责人: Jun Tan
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127058
• 关键词: Accounting; Adverse effects; Affect; Age; Age-Months; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloidosis; Anti-Inflammatory Agents; Anti-inflammatory; Biochemical; Brain; CD40 Ligand; Cells; Cerebrum; Clinical Trials; Cultured Cells; Data; Dementia; Deposition; Development; Dietary Supplementation; Diosmin; Direct Costs; Disease; Dose; Down-Regulation; Elderly; Facilities and Administrative Costs; Flavonoids; Foundations; Funding; Future; Generations; Health; Health Care Costs; Healthcare; Hela Cells; Human; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Life; Microglia; Molecular; Mus; Mutation; Neurons; Notch Signaling Pathway; Oral Administration; Pathogenesis; Pathology; Patients; Peptides; Phagocytosis; Phenotype; Phosphorylation; Process; Production; Prophylactic treatment; Reporting; Role; Signal Transduction; TNFRSF5 gene; Testing; Tg2576; Therapeutic; Therapeutic Effect; Time; Transgenic Mice; Transgenic Organisms; Up-Regulation; Work; aged; amyloid precursor protein processing; base; beta amyloid pathology; beta secretase; chemokine; cytokine; follow-up; gamma secretase; glial activation; hyperphosphorylated tau; improved; in vivo; inhibitor/antagonist; mouse model; neuroinflammation; notch protein; presenilin; response; tau Proteins; treatment group

 DESCRIPTION (provided by applicant): There may be a dual role of γ-secretase in AD. The cleavage of APP by γ-secretase is key in the pathogenesis of AD and amyloid accumulation in the brain. As such, γ-secretase has been targeted for years for development of AD therapies and γ-secretase inhibitors (GSIs). Most recently it was shown that a mutation in presenilin affecting γ-secretase activity may impair microglial phagocytosis of Aß and promote amyloid accumulation. Because GSIs may impair salutary microglia activity via inhibition of Notch signaling pathway, we seek to develop a new class of flavonoids GSIs that can reduce γ-APP cleavage yet minimize their potential negative effect on microglia phagocytosis activity. Optimally we would seek to do the former while promoting the latter. Turning to diosmin's efficacy as promoting both anti-amyloidogenic APP processing and microglial phagocytosis of Aß, we have recently shown that the treatment of Tg2576 mice with diosmin markedly reduces cerebral Aß40,42 species and consequently lowers Aß deposits. Based on this finding, its diosmetin metabolite becaome our focus on preliminary studies. These results indicate that diosmin/diosmetin not only reduces Aß by inhibiting γ-APP cleavage and decreases hyperphosphorylated tau by modulating GSK3ß activation, but also enhances microglial phagocytotic phenotype switching. In this proposal, flavonoid-diosmin will be orally administered to 3XTg-AD mice before (prophylactic treatment group) or after (therapeutic treatment group) development of AD-like pathology. Groups of untreated non-transgenic littermates will be compared to the transgenic treatment groups. Oral administration of diosmin to 3XTg-AD mice at 4 and 6 months of age will be performed for 6 months. Aim 1, we will sacrifice these mice at several ages to examine histological and biochemical endpoints and correlate pathological changes with improvement of cognitive impairment (funded by NCAAM). In this study, we plan to evaluate two time points comparing diosmin to control. Groups will be compared by their effects on opposing cognitive impairment and reducing AD-like pathology, including cerebral ß-amyloid deposits and tau hyperphosphorylation/NFT. AD is known to be accompanied by up-regulation of pro-inflammatory microglial responses manifested as the increased chemokine production by microglia. In addition, our preliminary data show that diosmin's metabolite, diosmetin induces anti-inflammatory phenotype through down-regulation of microglial CD40 signaling and resultant promotion of microglial phagocytosis of the aged Aß peptide. Thus in Aim 2, we will test the hypothesis that diosmin treatment preserves the pro-inflammatory phenotype in primary microglia isolated from young and aged 3XTg-AD mice. These studies could lay the foundation for AD clinical trials with diosmin diet supplementation in the near future.

 描述（由申请人提供）：γ-分泌酶在 AD 中可能具有双重作用。 γ-分泌酶对 APP 的裂解是 AD 发病机制和大脑中淀粉样蛋白积累的关键。因此，多年来，γ-分泌酶一直是 AD 疗法和 γ-分泌酶抑制剂 (GSI) 开发的目标。最近的研究表明，影响γ-分泌酶活性的早老素突变可能会损害小胶质细胞对Aβ的吞噬作用并促进淀粉样蛋白的积累。由于 GSI 可能通过抑制 Notch 信号通路损害有益的小胶质细胞活性，因此我们寻求开发一类新的黄酮类 GSI，它可以减少 γ-APP 裂解，同时最大限度地减少其对小胶质细胞吞噬活性的潜在负面影响。最理想的情况是，我们会在努力实现前者的同时促进后者。关于地奥司明促进抗淀粉样蛋白生成 APP 加工和小胶质细胞 Aß 吞噬作用的功效，我们最近表明，用地奥司明治疗 Tg2576 小鼠可显着减少大脑中的 Aß40,42 种类，从而降低 Aß 沉积。基于这一发现，其香叶木素代谢物成为我们前期研究的重点。这些结果表明，地奥司明/香木素不仅通过抑制 γ-APP 裂解来减少 Aß，通过调节 GSK3ß 激活来减少过度磷酸化的 tau，而且还增强小胶质细胞吞噬表型转换。在该提案中，将在AD样病理发生之前（预防性治疗组）或之后（治疗性治疗组）对3XTg-AD小鼠口服类黄酮-地奥司明。将未处理的非转基因同窝仔猪组与转基因处理组进行比较。对4个月和6个月大的3XTg-AD小鼠口服地奥司明，持续6个月。目标 1，我们将在几个年龄段处死这些小鼠，以检查组织学和生化终点，并将病理变化与认知障碍的改善联系起来（由 NCAAM 资助）。在本研究中，我们计划评估地奥司明与对照的两个时间点的比较。将比较各组对对抗认知障碍和减少 AD 样病理的影响，包括大脑 β-淀粉样蛋白沉积和 tau 蛋白过度磷酸化/NFT。已知 AD 伴随着促炎性小胶质细胞反应的上调，表现为小胶质细胞趋化因子产生的增加。此外，我们的初步数据表明，地奥司明的代谢物香叶木丁通过下调小胶质细胞 CD40 信号传导并由此促进小胶质细胞对老化 Aß 肽的吞噬作用来诱导抗炎表型。因此，在目标 2 中，我们将检验地奥司明治疗保留从年轻和老年 3XTg-AD 小鼠中分离的原代小胶质细胞中的促炎表型的假设。这些研究可以为不久的将来通过饮食补充地奥司明进行 AD 临床试验奠定基础。

项目成果

Human Umbilical Cord Blood Serum-derived α-Secretase: Functional Testing in Alzheimer's Disease Mouse Models.

• DOI: 10.1177/0963689718759473
• 发表时间: 2018-03
• 期刊: Cell transplantation
• 影响因子: 3.3
• 作者: Habib A;Hou H;Mori T;Tian J;Zeng J;Fan S;Giunta B;Sanberg PR;Sawmiller D;Tan J
• 通讯作者: Tan J