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

基本信息

批准号：
8976888
负责人：
Jun Tan
金额：
$ 22.43万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8976888
关键词：
Accounting Adverse effects Affect Age Age-Months Alzheimer&apos 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 Diet Diosmin Direct Costs Disease Dose Down-Regulation Elderly Facilities and Administrative Costs Flavonoids Foundations Funding Future Generations 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 Supplementation TNFRSF5 gene Testing Tg2576 Therapeutic Therapeutic Effect Time Transgenic Mice Transgenic Organisms Up-Regulation Work aged amyloid pathology amyloid precursor protein processing base chemokine cytokine follow-up gamma secretase hyperphosphorylated tau improved in vivo inhibitor/antagonist mouse model neuroinflammation notch protein presenilin public health relevance response secretase tau Proteins

项目摘要

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（通过应用证明）：γ-分泌酶在AD中的双重作用。针对AD疗法和γ-分泌酶抑制剂（GSIS）的针对性，CTINGγ-分泌性可能会损害Aß的小胶质吞噬作用，并通过抑制Notch信号途径对微胶质细胞的影响寻求对后者的效果。这些结果表明，通过调节GSK3ß激活的二粒/磷酸化tau，但在3xtg-AD小鼠（预防性治疗组）或之后，小胶质细胞型表型切换也会被口服。与转基因治疗组相比，在4个月和6个月大的时候，将二秒剂到3xtg-ad小鼠进行了6个月，我们将在严重和生物化学上牺牲小鼠。障碍（由NCAAM资助）。炎性表型的型型型型型tant促进了年龄Aß肽的小胶质细胞增多症。