A small molecule p75NTR ligand to treat post-stroke mixed dementia

混合性痴呆是一种复杂的痴呆形式，其中不同的疾病状态共存，最 常见的是血管性痴呆(VAD)的病理特征，如慢性卒中梗死，以及 阿尔茨海默病的病理特点。目前还不清楚到底有多少患者 被诊断为一种特定类型的痴呆症实际上是混合型痴呆症，然而尸检分析 提示这种情况可能存在于临床诊断为AD的近50%的患者中。然而，尽管 VaD和AD经常共存，但对这些疾病如何相互影响知之甚少，部分原因是 由于缺乏适当的混合性痴呆症动物模型，也没有经过验证的疾病修改疗法。 为了满足这一需求，这项提案的目标是测试一种一流的小分子口服生物利用度p75 神经营养素受体(P75NTR)配体LM11A-31，目前处于治疗AD的IIa期临床试验中， 对两种不同的中风后混合性痴呆小鼠模型也有疗效。第一，是创新模式 卒中后混合性痴呆，在卒中后几周，老龄野生型(Wt)小鼠表现出胆碱能 神经变性并出现与AD相似的神经性斑块(目标1)。这个 第二，是一种转基因混合痴呆小鼠模型，在该模型中，老年AβPPL/S小鼠经历了 与年龄匹配的患者相比，中风患者发展为更严重的AD病理(目标2)。在这两个模型中， 老鼠在中风后的几周内也会出现延迟性认知障碍。在这里取得的积极结果将 首次证实p75NTR是两种卒中后混合性痴呆模型的有效治疗靶点。 并可以快速进入中风后混合性痴呆症临床测试。

Mixed dementia is a complex form of dementia in which heterogeneous disease states co-­exist, the most common being pathologic characteristics of vascular dementia (VaD), such as chronic stroke infarcts, alongside pathologic characteristics of Alzheimer’s disease (AD). It is unknown precisely how many patients presently diagnosed with a particular type of dementia actually have mixed dementia, however post-­mortem analyses suggest that the condition may be present in nearly 50% of patients clinically diagnosed with AD. Yet despite the frequent co-­existence of VaD and AD, little is known about how these diseases influence each other, in part due to the lack of adequate animal models of mixed dementia, and there are no proven disease modifying therapies. To address this need, the goal of this proposal is to test if a first-­in-­class small molecule, orally bioavailable p75 neurotrophin receptor (p75NTR) ligand, LM11A-­31, currently in Phase IIa clinical trials for the treatment of AD, also has efficacy in two different mouse models of post-­stroke mixed dementia. The first, is an innovative model of post-­stroke mixed dementia in which in the weeks following stroke, aged wildtype (wt) mice exhibit cholinergic neurodegeneration along with the appearance of neuritic plaques resembling those found in AD (Aim 1). The second, is a transgenic mouse model of mixed dementia in which aged AβPPL/S mice that have undergone a stroke develop more severe AD pathology than their age-­matched counterparts (Aim 2). In both of these models, mice also develop delayed cognitive impairments in the weeks after stroke. Positive results obtained here would be the first validation that p75NTR is an effective therapeutic target in two post-­stroke mixed dementia models, and could fast-­track LM11A-­31 into post-­stroke mixed dementia clinical testing.