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

治疗中风后混合性痴呆的小分子 p75NTR 配体

基本信息

批准号：
9895609
负责人：
Thuy-Vi Vu Nguyen
金额：
$ 19.19万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895609
关键词：
Address Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid beta-Protein Animal Model Appearance Attenuated Autopsy Behavioral Bioavailable Biochemical Biological Assay Brain Characteristics Clinical Treatment Clinical Trials Cognitive Complex Degenerative Disorder Dementia Diagnosis Disease Disease model Down Syndrome Economic Burden Exhibits Experimental Designs Female Goals Harvest Hippocampus (Brain)Histologic Huntington Disease Impaired cognition Individual Infarction Inflammatory Inflammatory Response Ligands Modeling Mus NGFR Protein Nerve Degeneration Nerve Growth Factors Neurons Oral Oral Administration Outcome Pathologic Pathology Patients Phase Phosphorylation Play Recording of previous events Recovery Research Risk Role Senile Plaques Signal Transduction Signaling Molecule Stroke Testing Therapeutic Transgenic Mice Treatment Efficacy Validation Vascular Dementia Wild Type Mouse aged basal forebrain behavior test cerebrovascular cerebrovascular pathology chemokine cholinergic chronic stroke clinical Diagnosis cognitive function cytokine experience improved innovation interest male mimetics mixed dementia motor deficit mouse model neuroinflammation neuropathology novel therapeutics post stroke post stroke dementia prevent psychologic research clinical testing sham surgery small molecule stroke model stroke risk tau Proteins therapeutic target treatment guidelines β-amyloid burden

项目摘要

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.

混合性痴呆是一种复杂的痴呆形式，其中异质性疾病状态共存，最常见的是混合性痴呆。常见的是血管性痴呆（VaD）的病理特征，如慢性中风梗塞，阿尔茨海默病（AD）的病理特征。目前尚不清楚有多少患者被诊断患有某种特定类型的痴呆症的人实际上患有混合型痴呆症，表明该病症可能存在于近50%的临床诊断为AD的患者中。然而，尽管 VaD和AD频繁共存，但对这些疾病如何相互影响知之甚少，部分原因是缺乏足够的混合性痴呆动物模型，也没有经过证实的疾病改善疗法。为了满足这一需求，本提案的目标是测试第一种生物可利用的小分子，口服生物可利用的p75，神经营养因子受体（p75 NTR）配体，LM 11 A-LM 31，目前处于治疗AD的IIa期临床试验中，在两种不同的中风后混合性痴呆小鼠模型中也有效。第一，是创新模式在中风后的几周内，老年野生型（wt）小鼠表现出胆碱能神经变性沿着神经炎斑块的出现，类似于AD中发现的那些（目的1）。的第二种是混合性痴呆的转基因小鼠模型，其中老年AβPPL/S小鼠经历了一个中风患者比同龄人发展出更严重AD病理（Aim 2）。在这两种模式中，小鼠在中风后的几周内也会出现延迟的认知障碍。在此获得的积极成果将首次证实p75 NTR是两种脑卒中后混合痴呆模型中的有效治疗靶点，并可快速跟踪LM 11 A-131进入脑卒中后混合性痴呆的临床试验。