Abeta42 Altering Compounds: Mechanisms of Action

Abeta42 改变化合物：作用机制

• 批准号: 7533387
• 负责人: Todd E Golde
• 金额: $ 53.27万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533387
• 关键词: Abeta synthesis; Affinity; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Basic Science; Benzophenones; Binding; Binding Sites; Brain; Chimeric Proteins; Chronic; Class; Clinic; Clinical Research; Collaborations; Complex; Data; Dementia; Deposition; Development; Dose; Elderly; Elevation; Future; Grant; Ibuprofen; In Vitro; Laboratories; Ligands; Link; Membrane; Methodology; Molecular Conformation; Mus; Naproxen; Neonatal; Nimesulide; Non-Steroidal Anti-Inflammatory Agents; Numbers; Pathology; Peptides; Pharmaceutical Preparations; Positioning Attribute; Production; Prostaglandin-Endoperoxide Synthase; Public Health; Range; Rate; Recombinants; Relative (related person); Reporting; Site; Slice; Synaptic Transmission; Testing; Tg2576; Therapeutic; Transgenic Organisms; Uncertainty; Virus; Work; abeta accumulation; abeta deposition; base; benzophenone; crosslink; cyclooxygenase 1; gamma secretase; in vivo; inhibitor/antagonist; insight; mouse model; novel; prevent; protective effect; recombinant virus; secretase

DESCRIPTION (provided by applicant): A great deal of evidence supports the hypothesis that selective targeting of Abeta42 may be an ideal therapeutic strategy to prevent and possibly treat Alzheimer's disease (AD), the major cause of dementia among the elderly. We have previously reported that select NSAIDS were capable of selectively modulating Abeta42. More recently, we have found that numerous compounds increase Abeta42. Abeta42 modulating agents (generically referred to as gamma-secretase modulators or GSMs) minimally alter total Abeta production but shift the gamma-secretase cleavage site. Abeta42 lowering GSMs increase the production of shorter Abeta peptides and raising agents decrease the levels of shorter Abeta peptides. Current data using novel photoaffinity ligands that modulate Abeta42 cleavage indicate that Abeta42 modulating agents alter production and aggregation of Abeta by binding to a site within the Abeta region of APP carboxyl terminal fragments (CTFs). We hypothesize that binding of the Abeta region of APP CTFs alters the conformation of the APP CTF or its position in the membrane resulting in altered gamma-secretase cleavage, and following cleavage compound binding alters Abeta aggregation. We outline a number of studies to extend our current data that support this hypothesis. We will also evaluate the linked hypotheses regarding the in vivo mechanism of action of Abeta42 lowering NSAIDs and other Abeta42 altering agents. We will perform chronic dosing studies with drug-like Abeta42 lowering and raising agents in APP and BRI-Abeta42 mouse models to evaluate the relative contribution of altering Abeta42 production vs. altering aggregation with respect to effect on Abeta loads and other AD-like pathologies. We will also determine if elevations in shorter Abeta peptides are protective. For these later studies we will use recombinant adenoassociated virus (rAAV) to deliver BRI-Abeta fusion constructs encoding Abeta 1-34, 1-37, and 1-38 to the brain of neonatal APP mice. This methodology creates "somatic brain transgenics" and will allow us to rapidly evaluate the effects of shorter Abeta peptides on Abeta deposition. Effects on Abeta deposition and synaptic transmission will be evaluated. The influence of shorter Abeta peptides on Abeta42 aggregation in vitro will also be evaluated in vitro. These studies should provide additional insight into the mechanisms whereby Abeta42 modulating agents shift Abeta cleavage and how they exert their protective effects in vivo. PUBLIC HEALTH RELEVANCE: A great deal of evidence supports the hypothesis that selective targeting of Abeta42 may be an ideal therapeutic strategy to prevent and possibly treat Alzheimer's disease (AD), the major cause of dementia among the elderly. The proposed studies should provide additional insight into the mechanisms whereby Abeta42 modulating agents shift Abeta cleavage and how they exert their protective effects in vivo. These studies will thereby inform future therapeutic development of this class of potential AD therapeutics.

描述（由申请人提供）：大量证据支持以下假设：ABETA42的选择性靶向可能是预防和治疗阿尔茨海默氏病（AD）的理想治疗策略，这是老年人痴呆的主要原因。我们以前已经报道了某些NSAID能够选择性调节Abeta42。最近，我们发现许多化合物会增加Abeta42。 ABETA42调节剂（通常称为γ-分泌酶调节剂或GSMS）最小改变了总ABETA的产生，但会改变伽马 - 分泌酶的裂解位点。 ABETA42降低GSM会增加较短的Abeta肽的产生，并升高剂降低了较短的Abeta肽的水平。使用新型的光亲和力配体调节Abeta42裂解的当前数据表明，ABETA42调节药物通过与App Carboxyl末端碎片（CTFS）Abeta区域内的位点结合来改变ABETA的产生和聚集。我们假设APP CTF的ABETA区域的结合改变了APP CTF或其在膜中的位置，从而改变了γ-分泌酶的切割改变，并随后切割化合物结合结合改变了Abeta的聚集。我们概述了许多研究，以扩展我们的当前数据支持这一假设。我们还将评估有关Abeta42降低NSAID和其他Abeta42改变剂的体内作用机理的链接假设。我们将使用APP和BRI-ABETA42小鼠模型中的类似药物的Abeta42降低和升高剂进行慢性剂量研究，以评估改变Abeta42生产的相对贡献与改变聚集有关对ABETA负载和其他AD类病理学的影响。我们还将确定较短的Abeta肽的高程是否具有保护性。在这些后来的研究中，我们将使用重组腺体相关病毒（RAAV）提供编码Abeta 1-34、1-37和1-38的Bri-Abeta融合构建体，以向Neonatal App小鼠的大脑提供。这种方法创建了“体细胞转基因”，将使我们能够快速评估较短的Abeta肽对Abeta沉积的影响。将评估对Abeta沉积和突触传播的影响。较短的Abeta肽对体外ABETA42聚集的影响也将在体外评估。这些研究应提供对Abeta42调节药物转移Abeta裂解以及它们如何在体内发挥保护作用的机制的更多见解。公共卫生相关性：大量证据支持以下假设：选择性靶向Abeta42可能是预防和治疗老年人痴呆症的主要原因的理想治疗策略。拟议的研究应提供对Abeta42调节药物转移Abeta裂解以及它们如何在体内发挥保护作用的机制的更多见解。这些研究将为这类潜在的AD治疗剂的未来治疗发展提供信息。