P75NTR Small Molecule Ligands for Down Syndrome Therapy

描述（由申请人提供）：本申请题为“P75 NTR Small Molecule Ligands for Down Syndrome Therapy”，是对NINDS转化研究探索/开发项目（R21;项目公告：PAR-11-293）的回应。目前的提议将测试p75神经营养因子受体（p75 NTR）的小分子配体是否能有效治疗唐氏综合征（DS）相关的神经变性。与DS最显著相关的改变是神经生长因子的减少，神经生长因子结合基底前脑胆碱能神经元（BFCN）表达的p75 NTR，其变性是该病症的病理标志。Longo实验室先前发现，由申请人及其同事开发的p75 NTR配体可预防阿尔茨海默病（AD）小鼠模型中的BFCN萎缩和认知缺陷。迄今为止，还没有已知的小分子能够恢复对BFCN的营养支持，在特定的靶受体处起作用，通过口服给药穿透血脑屏障，并且没有不良的副作用。因此，这些新的p75 NTR配体现在准备在DS中进行功效测试。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的病理学和40岁时AD型痴呆的显著患病率。拟议的研究将使用DS的转基因小鼠模型来执行两个目标：（i）使用一系列行为测试来确定两种（先导和备用）p75 NTR配体是否会减缓或预防与DS相关的记忆缺陷的出现;以及（ii）测试p75 NTR配体是否改善经典的DS相关胆碱能神经病理学。这些研究的阳性结果将确定一种新的可行的治疗策略，用于减少目前无法治疗的标志性DS表型。当前的R21提案旨在提供概念验证和靶标验证数据，以支持后续的U 01申请，以确定这些新型小分子p75 NTR配体对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.