Abeta42 Altering Compounds: Mechanisms of Action

描述（由申请人提供）：大量证据支持以下假设，即选择性靶向Abeta 42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。我们以前曾报道，选择NSAIDS能够选择性地调节A β 42。最近，我们发现许多化合物增加了A β 42。A β 42调节剂（一般称为γ-分泌酶调节剂或GSM）最小程度地改变总A β产生，但移动γ-分泌酶切割位点。降低A β 42的GSM增加较短A β肽的产生，而升高剂降低较短A β肽的水平。使用调节A β 42切割的新型光亲和配体的当前数据表明，A β 42调节剂通过结合APP羧基末端片段（CTF）的A β区域内的位点来改变A β的产生和聚集。我们假设APP CTF的Abeta区域的结合改变了APP CTF的构象或其在膜中的位置，导致γ-分泌酶切割改变，并且切割后化合物结合改变了Abeta聚集。我们概述了一些研究，以扩展我们目前的数据，支持这一假设。我们还将评估关于降低A β 42的NSAID和其他A β 42改变剂的体内作用机制的相关假设。我们将在APP和BRI-Abeta 42小鼠模型中使用药物样Abeta 42降低剂和升高剂进行长期给药研究，以评价改变Abeta 42产生与改变聚集相对于对Abeta 42负荷和其他AD样病理的影响的相对贡献。我们还将确定较短的Abeta肽的升高是否具有保护作用。对于这些随后的研究，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融合构建体递送至新生APP小鼠的脑。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Abeta肽对Abeta沉积的影响。将评价对Abeta沉积和突触传递的影响。还将在体外评价较短的Abeta肽对Abeta 42体外聚集的影响。这些研究应该提供额外的洞察机制，其中Abeta 42调节剂转移Abeta裂解，以及它们如何发挥其体内保护作用。公共卫生相关性：大量证据支持这样的假设，即选择性靶向Abeta 42可能是预防和可能治疗老年痴呆症（AD）的理想治疗策略。拟议的研究应该提供更多的了解Abeta 42调节剂改变Abeta裂解的机制，以及它们如何在体内发挥保护作用。因此，这些研究将为这类潜在AD治疗剂的未来治疗开发提供信息。

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.