P75NTR Small Molecule Ligands for Down Syndrome Therapy

描述（由申请人提供）：这份题为“用于唐氏综合征治疗的P75NTR小分子配体”的申请是对NINDS转化研究探索性/发展性项目（R21；项目公告：PAR-11-293）的回应。目前的提案将测试p75神经营养因子受体（p75NTR）的小分子配体是否能有效治疗唐氏综合征（DS）相关的神经退行性变。与退行性痴呆最显著相关的改变是神经生长因子的减少，该因子与基底前脑胆碱能神经元（BFCN）表达的p75NTR结合，其变性是该疾病的病理标志。Longo实验室先前发现，由申请人及其同事开发的p75NTR配体可以预防阿尔茨海默病（AD）小鼠模型中BFCN的萎缩和认知缺陷。迄今为止，还没有一种已知的小分子能够恢复BFCN的营养支持，在特定的靶受体上起作用，通过口服给药穿透血脑屏障，并且没有不良副作用。因此，这些新的p75NTR配体现在准备在DS中进行疗效测试。除了对神经发育的有害影响外，退行性痴呆还具有神经退行性后果，包括类似AD的病理和AD型痴呆在生命的第四个十年的显著流行。拟议的研究将使用转基因小鼠DS模型来实现两个目标：(i)通过一系列行为测试确定两种p75NTR配体（铅和备用）是否会减缓或预防与DS相关的记忆缺陷的出现；（ii）检测p75NTR配体是否改善了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标验证数据，以支持随后的U01申请，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.