Flavonoid-diosmin modulation of Abeta and tau pathologies through GSK-3 signaling

类黄酮-地奥司明通过 GSK-3 信号传导调节 Abeta 和 tau 病理学

• 批准号: 8627446
• 负责人: Jun Tan
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627446
• 关键词: Accounting; Adverse effects; Affect; Age; Age-Months; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Anti-Inflammatory Agents; Anti-inflammatory; Behavior; Biochemical; Brain; CD40 Ligand; Cells; Cerebrum; Chronic; Clinical Trials; Cognitive; Cultured Cells; Cytokine Signaling; Dementia; Deposition; Development; Diet; Diosmin; Direct Costs; Disease; Dose; Elderly; Facilities and Administrative Costs; Flavonoids; Foundations; Frequencies; Future; Generations; Glycogen Synthase Kinase 3; Health Care Costs; Healthcare; Hela Cells; Human; Impaired cognition; Impairment; In Vitro; Individual; Inflammation; Inflammatory Response; Interferons; Life; Memory; Microglia; Molecular Weight; Mus; Mutation; Neurocognition; Neurons; Notch Signaling Pathway; Oral Administration; Pathogenesis; Pathology; Patients; Performance; Phagocytosis; Phenotype; Phosphorylation; Prevalence; Process; Production; Prophylactic treatment; Reporting; Role; Signal Transduction; Supplementation; TNFRSF5 gene; Testing; Tg2576; Therapeutic; Therapeutic Effect; Transgenic Organisms; Work; aged; amyloid pathology; amyloid precursor protein processing; base; follow-up; hyperphosphorylated tau; improved; in vivo; inhibitor/antagonist; mouse model; neuroinflammation; notch protein; peptide A; presenilin; public health relevance; response; secretase; tau Proteins; therapeutic effectiveness; transgenic model of alzheimer disease

DESCRIPTION (provided by applicant): There may be a dual role of ?-secretase in AD. The cleavage of APP by ?-secretase is key in the pathogenesis of AD and amyloid accumulation in the brain. As such, ?-secretase has been targeted for years for development of AD therapies and ?-secretase inhibitors (GSIs). Most recently it was shown that a mutation in presenilin affecting ?-secretase activity may impair microglial phagocytosis of A? 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 ?-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 phagcytosis of A?? we have recently shown that the treatment of Tg2576 mice with diosmin markedly reduces cerebral A?40,42 species and consequently lowers A? deposits. Based on this finding, its diosmetin metabolite becomes our focus on preliminary studies. These results indicate that diosmin/diosmetin not only reduces A? by inhibiting ?-APP cleavage but also decreases hyperphosphorylated tau by modulating GSK-3? activation and enhances microglial anti-inflammatory and phagocytotic phenotype switching. These new results fully support our present hypothesis that diosmin could have a therapeutic effect in AD by reducing cognitive impairment while also reducing cerebral ?-amyloid levels, tau pathology and microglial/neuroinflammation. In this application, the 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 these mice will begin at 4 and 6 months of age and continued for 6 months. For Aim 1, cognitive testing will be done at several ages following the administration. For Aim 2, we will sacrifice these mice at several ages to examine histological and biochemical endpoints related to amyloid deposition and tau hyperphosphorylation and correlate pathological changes with cognitive performance. For Aim 3, we will test the hypothesis that diosmin treatment preserves the anti-inflammatory and phagocytic phenotype in primary microglia 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）：可能有双重作用？- AD分泌酶APP的切割由？-分泌酶是AD发病机制和脑中淀粉样蛋白积累的关键。因此，？多年来，分泌酶一直是开发AD疗法的目标，分泌酶抑制剂（GSI）。最近的研究表明，早老素的突变影响？分泌酶活性可能会损害小胶质细胞的吞噬A？并促进淀粉样蛋白积累。由于GSIs可能通过抑制Notch信号通路损害有益的小胶质细胞活性，我们寻求开发一类新的类黄酮GSIs，可以减少？APP切割还使其对小胶质细胞吞噬活性的潜在负面影响最小化。最理想的情况是，我们将寻求在促进后者的同时做到前者。至于地奥司明促进抗淀粉样蛋白生成APP加工和小胶质细胞吞噬A？？我们最近发现用地奥司明治疗Tg2576小鼠可显著降低脑A？40，42物种，从而降低A？存款基于这一发现，其代谢产物薯蓣皂苷成为我们的重点进行了初步研究。这些结果表明，地奥司明/diosmetin不仅减少A？通过抑制？APP切割，但也减少过度磷酸化的tau蛋白通过调节GSK-3？激活并增强小胶质细胞抗炎和吞噬表型转换。这些新的结果完全支持我们目前的假设，即地奥司明可以通过减少认知障碍，同时也减少脑缺血，对AD有治疗作用。淀粉样蛋白水平、tau病理学和小胶质细胞/神经炎症。 在本申请中，类黄酮-地奥司明将在AD样病理学发展之前（预防性治疗组）或之后（治疗性治疗组）口服给予3XTg-AD小鼠。将未处理的非转基因同窝仔组与转基因处理组进行比较。这些小鼠将在4月龄和6月龄时开始经口给予地奥司明，并持续6个月。对于目标1，将在给药后的几个年龄段进行认知测试。对于目标2，我们将在几个年龄处死这些小鼠，以检查与淀粉样蛋白沉积和tau过度磷酸化相关的组织学和生化终点，并将病理变化与认知表现相关联。对于目标3，我们将检验地奥司明治疗保留来自年轻和老年3XTg-AD小鼠的原代小胶质细胞中的抗炎和吞噬细胞表型的假设。这些研究可为不久的将来进行地奥司明饮食补充的AD临床试验奠定基础。