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

描述（由申请人提供）：可能有双重角色？- AD分泌酶。APP的切割由？-分泌酶是AD发病机制和脑内淀粉样蛋白积累的关键。因此，？分泌酶多年来一直是阿尔茨海默病治疗的靶标。分泌酶抑制剂（GSIs）最近有研究表明，早老素的突变会影响？分泌酶活性可能损害小胶质细胞吞噬A？并促进淀粉样蛋白的积累。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的裂解，并尽量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，我们将在促进后者的同时努力实现前者。至于地奥司明在促进抗淀粉样变性APP加工和A?？我们最近的研究表明，用地奥司明治疗Tg2576小鼠可显著降低脑A？40,42种，因此降低A？存款。基于这一发现，其薯蓣皂苷代谢物成为我们初步研究的重点。这些结果表明薯蓣皂苷/薯蓣皂苷不仅能降低A？通过抑制？-APP裂解，但也减少过度磷酸化的tau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。这些新结果完全支持了我们目前的假设，即地奥米明可以通过减少认知障碍同时降低大脑？-淀粉样蛋白水平，tau病理学和小胶质/神经炎症。在本研究中，在3XTg-AD小鼠出现ad样病理之前（预防性治疗组）或之后（治疗性治疗组）口服类黄酮-地奥司明。将未经处理的非转基因幼崽组与转基因处理组进行比较。这些小鼠将在4和6个月大时开始口服地奥司明，并持续6个月。对于Aim 1，认知测试将在给药后的几个年龄段进行。在aims 2中，我们将在不同年龄的小鼠中进行牺牲，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联系起来。在Aim 3中，我们将验证地奥明治疗保留了年轻和老年3XTg-AD小鼠的初级小胶质细胞的抗炎和吞噬表型的假设。这些研究可以为将来补充地奥米明的AD临床试验奠定基础。

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.