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）：AD中可能存在？ - 分泌酶的双重作用。 APP通过？分泌酶的裂解是大脑中AD和淀粉样蛋白积累发病机理的关键。因此，？ - 分泌酶多年来一直针对开发AD疗法和 - 分泌酶抑制剂（GSIS）。最近，结果表明，促蛋白蛋白的突变会影响 - 分泌酶活性可能会损害A的小胶质细胞增多症？并促进淀粉样蛋白积累。由于GSIS可能会通过抑制Notch信号传导途径损害有益的小胶质细胞活性，因此我们试图开发一类新的类黄酮GSIS，可以减少？ - APP裂解，但最大程度地减少其对小胶质细胞吞噬作用的潜在负面影响。最佳情况下，我们将寻求在推广后者的同时做前者。转向diosmin的疗效，以促进A？我们最近表明，用Diosmin的TG2576小鼠的治疗显着降低了脑A？40,42种，因此降低了A？沉积物。基于这一发现，其二胺代谢产物成为我们对初步研究的关注。这些结果表明二敏/二胺不仅降低了A吗？通过抑制？App裂解，但也通过调节GSK-3来减少高磷酸化的Tau？激活和增强小胶质细胞抗炎和吞噬表型切换。这些新的结果完全支持了我们目前的假设，即通过减少认知障碍，同时还会降低大脑？ - 淀粉样蛋白水平，tau病理学和小胶质细胞/神经炎症，对AD具有治疗作用。 在此应用中，类黄酮二氨基蛋白将在（预防性治疗组）之前或（治疗治疗组）开发AD样病理学之前口服给3XTG-AD小鼠。将未经处理的非转基因同窝仔与转基因治疗组进行比较。对这些小鼠的口服二杀剂将在4个月和6个月大开始持续6个月。对于AIM 1，管理后将在几个年龄进行认知测试。对于AIM 2，我们将在几个年龄段牺牲这些小鼠，以检查与淀粉样沉积和TAU高磷酸化有关的组织学和生化终点，并将病理变化与认知性能相关。对于AIM 3，我们将测试以下假设：Diosmin治疗可保留年轻和年龄3xTG-AD小鼠的原代小胶质细胞中抗炎和吞噬表型。这些研究可以在不久的将来补充Diosmin饮食的AD临床试验基础。