Testing a therapeutic strategy for hippocampal sclerosis of aging, a key AD mimic

 描述（由申请人提供）：类似阿尔茨海默病（AD）的疾病是老年人认知障碍的原因。对这些疾病的认识不足阻碍了AD的临床试验，同时从临床研究的角度来看，重要的疾病基本上没有得到解决。常见且高发病率的“AD模拟物”是老化的海马硬化（HS-Aging）。HS老化的特征在于海马中的细胞损失和星形细胞增多，具有磷酸化TDP-43（P-TDP-43）病理学，与AD型病理学无关，也与APOE基因型无关。HS老化影响10-25%的85岁以上的人。当前提案的PI广泛研究了HS-老化，包括第一个HS-老化全基因组关联研究（GWAS）。ABCC 9基因的遗传多态性与HS-衰老病理学有关。重要的是，我们最近（2015年1月）发表了一篇论文，在另一组研究志愿者中重复了这一观察结果。ABCC 9突变使我们能够解决基因组学研究尚未实现的核心承诺：临床相关性。值得注意的是，GWAS鉴定的HS-衰老风险基因ABCC 9是一个“可药物化的靶标”-激动剂和拮抗剂药物都广泛用于人类。在之前发表的一项研究中，我们发现暴露于磺酰脲类药物（拮抗ABCC 9蛋白功能的口服抗糖尿病药物）与人类HS-衰老病理学风险增加相关，控制其他因素。我们需要评估在临床前模型中靶向ABCC 9的潜力，以更严格地控制实验参数。这将使我们能够测试ABCC 9激动剂药物的影响，与磺酰脲类药物的相反作用，作为临床HS老化的潜在疗法。总体假设：药理学ABCC 9调节为HS老化提供了治疗策略。我们提出了概念验证临床前研究，以检验ABCC 9激动剂尼可地尔在小鼠模型中减弱HS老化的病理和行为特征的特定假设。具体目标：1。表征HS老化的第一个临床前模型。在GRN敲除（GRN-KO）小鼠中，我们的研究表明存在模拟人类HS老化特征的脑变化，包括海马P-TDP-43病理学和海马相关的神经行为缺陷。2.基于人体研究，在GRN-KO小鼠模型中检验了拮抗ABCC 9的磺酰脲类药物（格列美脲）加重HS-衰老病理学和异常行为的假设。3.在GRN-KO小鼠模型中检验尼可地尔打开钾通道（与磺酰脲类药物活性相反）可减少HS-衰老相关异常病理和行为的假设。由于存在相似的病理学和遗传易感性，治疗策略也可能与单独的致死性神经退行性疾病额颞叶变性（FTLD）相关。

 DESCRIPTION (provided by applicant): Diseases that mimic Alzheimer's disease (AD) are understudied causes of cognitive impairment in the elderly. Poor understanding of these diseases has hampered AD clinical trials while leaving important illnesses largely unaddressed from a clinical research perspective. A common and high-morbidity "AD mimic" is hippocampal sclerosis of aging (HS-Aging). HS-Aging is characterized by cell loss and astrocytosis in the hippocampus, with phosphorylated TDP-43 (P-TDP-43) pathology, not correlated with AD-type pathology, nor with APOE genotype. HS-Aging affects 10-25% of persons above age 85 years. The PI of the current proposal has studied HS-Aging extensively, including the first HS-Aging genome-wide association study (GWAS). A genetic polymorphism in the ABCC9 gene is linked to HS-Aging pathology. Importantly, we recently (Jan 2015) published a paper that replicated this observation in a separate group of research volunteers. The ABCC9 mutation enables us to address a central as-yet unrealized promise of genomics studies: clinical relevance. Remarkably, the GWAS-identified HS-Aging risk gene ABCC9 is a "druggable target"-both agonist and antagonist drugs are used widely in humans. In a prior published study, we found that exposure to sulfonylureas (oral anti-diabetic drugs that antagonize ABCC9 protein function) is associated with increased risk for HS-Aging pathology in humans, controlling for other factors. We need to assess the potential to target ABCC9 in a preclinical model for more rigorous control of experimental parameters. That will enable us to test the impact of an ABCC9 agonist drug, with the opposite effects of sulfonylureas, as a potential therapy for clinical HS-Aging. Overall Hypothesis: Pharmacologic ABCC9 regulation provides a therapeutic strategy for HS-Aging. We propose proof-of-concept preclinical studies to test the specific hypothesis that ABCC9 agonist nicorandil attenuates pathologic and behavioral features of HS-Aging in a mouse model. Specific Aims: 1. Characterize the first preclinical model of HS-Aging. In GRN knockout (GRN-KO) mice, our studies indicate the presence of brain changes that model features of human HS-Aging, including hippocampal P-TDP-43 pathology and hippocampus-related neurobehavioral deficits. 2. Based on studies in humans, test in the GRN-KO mouse model the hypothesis that a sulfonylurea drug (glimepiride) which antagonizes ABCC9, exacerbates HS-Aging pathology and abnormal behavior. 3. Test in the GRN-KO mouse model the hypothesis that nicorandil, which opens the potassium channel (the opposite activity as sulfonylureas), reduces HS-Aging-related abnormal pathology and behavior. Since there are similar pathologies and genetic susceptibilities, the therapeutic strategy may also be relevant to a separate lethal neurodegenerative disease, frontotemporal lobar degeneration (FTLD).