P75NTR Small Molecule Ligands for Down Syndrome Therapy

描述(申请人提供)：这项名为“用于治疗唐氏综合症的p75NTR小分子配体”的申请是对NINDS在翻译研究(R21；计划公告：PAR-11-293)中的探索/开发项目的响应。目前的提议将测试p75神经营养素受体(P75NTR)的小分子配体是否将有效治疗与唐氏综合症(DS)相关的神经退行性变。与DS相关的一个最显著的变化是神经生长因子的减少，它与基底前脑胆碱能神经元(BFCN)表达的p75NTR结合，BFCN的变性是该疾病的一个病理标志。Longo实验室之前发现，由申请人和他的同事开发的p75NTR配体可以防止BFCN的萎缩和阿尔茨海默病(AD)小鼠模型的认知缺陷。到目前为止，还没有已知的小分子能够恢复对BFCN的营养支持，作用于特定的靶受体，通过口服穿过血脑屏障，并且缺乏不良副作用。因此，这些新的p75NTR配体现在准备在DS中进行有效性测试。除了对神经发育的有害影响外，DS还具有神经退行性后果，包括类似AD的病理和在生命的第四个十年显著流行的AD类型痴呆。拟议的研究将使用DS的转基因小鼠模型来实现两个目标：(I)通过一系列行为测试，确定两个(主导和备用)p75NTR配体是否将减缓或防止与DS相关的记忆缺陷的出现；以及(Ii)测试p75NTR配体是否可以改善与DS相关的经典胆碱能神经病理。这些研究的积极结果将确定一种新的可行的治疗策略，以减少目前无法治疗的标志性DS表型。目前的R21提案旨在提供概念验证和靶向验证数据，这些数据将支持后续的U01应用，以确定这些新型小分子p75NTR配体对抗DS的有效性。

DESCRIPTION (provided by applicant): This application titled "P75NTR Small Molecule Ligands for Down Syndrome Therapy" is in response to NINDS Exploratory/Developmental Projects in Translational Reseach (R21; program announcement: PAR-11-293). The current proposal will test whether small molecule ligands for the p75 neurotrophin receptor (p75NTR) will be effective treatments for neurodegeneration associated with Down syndrome (DS). An alteration most notably associated with DS is reduction of nerve growth factor, which binds to p75NTR expressed by basal forebrain cholinergic neurons (BFCN), the degeneration of which is a pathological hallmark of the disorder. The Longo laboratory previously found that p75NTR ligands, developed by the applicant and his colleague, prevent atrophy of BFCN and cognitive deficits in a mouse model of Alzheimer's disease (AD). To date, there is no known small molecule capable of restoring trophic support to BFCN, functioning at a specific target receptor, penetrating the blood brain barrier via oral administration, and lacking undesirable side-effects. Thus, these novel p75NTR ligands are now poised for efficacy testing in DS. In addition to deleterious effect on neurodevelopment, DS has neurodegenerative consequences that include pathology resembling AD and a significant prevalence of AD-type dementia in the fourth decade of life. The proposed studies will use a transgenic mouse model of DS to execute two aims: (i) determine if two (lead and backup) p75NTR ligands will slow the emergence of, or prevent, memory deficits associated with DS using a battery of behavioral tests; and (ii) test whether p75NTR ligands ameliorate classic DS-related cholinergic neuropathology. Positive results in these studies will identify a novel and feasible therapeutic strategy for reducing hallmark DS phenotypes, which are currently untreatable. The current R21 proposal is designed to provide proof-of-concept and target validation data that will support a subsequent U01 application to determine the effectiveness of these novel small molecule p75NTR ligands against DS.