Abeta42 Altering Compounds: Mechanisms of Action

描述（由申请人提供）：大量证据支持这一假设，即选择性靶向Abeta42可能是预防甚至可能治疗老年痴呆症的主要原因阿尔茨海默病（AD）的理想治疗策略。我们之前报道过选择性非甾体抗炎药能够选择性地调节Abeta42。最近，我们发现许多化合物增加了Abeta42。Abeta42调节剂（通常被称为γ -分泌酶调节剂或gsm）可以最小程度地改变总β的产生，但可以改变γ -分泌酶的裂解位点。降低Abeta42的GSMs增加了短β肽的产生，而升高剂降低了短β肽的水平。目前使用新型光亲和配体调节Abeta42切割的数据表明，Abeta42调节剂通过结合APP羧基末端片段（CTFs）的Abeta区域内的一个位点来改变Abeta的产生和聚集。我们假设APP CTF的β区结合改变了APP CTF的构象或其在膜上的位置，从而改变了γ -分泌酶的切割，而切割后的化合物结合改变了β聚集。我们概述了一些研究，以扩展我们目前支持这一假设的数据。我们还将评估关于降低Abeta42的非甾体抗炎药和其他Abeta42改变剂的体内作用机制的相关假设。我们将在APP和brii -Abeta42小鼠模型中进行药物样Abeta42降低和升高剂的慢性给药研究，以评估改变Abeta42产生与改变Abeta42聚集对Abeta负荷和其他ad样病理的影响的相对贡献。我们还将确定短β肽的升高是否具有保护作用。在这些后期的研究中，我们将使用重组腺相关病毒（rAAV）将编码Abeta 1-34、1-37和1-38的BRI-Abeta融合构建体传递到新生APP小鼠的大脑。这种方法创造了“体细胞脑转基因”，并将使我们能够快速评估较短的β肽对β沉积的影响。对β沉积和突触传递的影响将被评估。短肽对Abeta42体外聚集的影响也将在体外进行评估。这些研究应该为Abeta42调节剂改变Abeta42切割的机制以及它们如何在体内发挥保护作用提供更多的见解。公共卫生相关性：大量证据支持这一假设，即选择性靶向Abeta42可能是预防和可能治疗阿尔茨海默病（AD）的理想治疗策略，AD是老年人痴呆的主要原因。拟议的研究应该为Abeta42调节剂改变Abeta42切割的机制以及它们如何在体内发挥其保护作用提供更多的见解。因此，这些研究将为这类潜在的阿尔茨海默病治疗方法的未来治疗发展提供信息。

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.