Novel pathogenetic mechanism for hippocampal sclerosis, a common Alzheimers mimic

海马硬化的新发病机制，一种常见的阿尔茨海默病模拟

• 批准号: 9402752
• 负责人: PETER T. NELSON
• 金额: $ 45.86万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402752
• 关键词: ABCC9 gene; Affect; Age; Aging; Agonist; Alzheimer' s Disease; American; Area; Astrocytes; Autopsy; Behavior; Biological Markers; Biometry; Blood specimen; Brain; Brain Diseases; Brain Pathology; Cell Culture Techniques; Cells; Clinical; Cognitive; DNA; Data; Databases; Dementia; Development; Diagnosis; Disease; Elderly; Exhibits; Functional disorder; Future; Gene Expression; Genes; Genetic; Genotype; Glimepiride; Goals; Hippocampus (Brain); Hormone Responsive; Human; Impaired cognition; Individual; Infarction; Interdisciplinary Study; Kentucky; Knockout Mice; Knowledge; Life; Link; Metformin; Methods; Modeling; Morbidity - disease rate; Mus; Mutation; Neurofibrillary Tangles; Oral; Pathogenesis; Pathologic; Pathology; Patient Self-Report; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Regulator Genes; Research; Research Personnel; Risk; Sampling; Severities; Spinal Puncture; Testing; Therapeutic; Thyroid Gland; Thyroid Hormones; Thyroxine; Transcript; Triiodothyronine; Universities; Widespread Disease; aged; base; biobank; cell transformation; clinical biomarkers; cohort; digital; experimental study; genetic variant; genomic biomarker; hippocampal sclerosis; human embryonic stem cell; human genomics; in vivo; neurobehavior; neuropathology; novel; novel marker; prevent; programs; protein TDP-43; risk variant; synucleinopathy; therapeutic target

Hippocampal sclerosis of aging (HS-Aging) is a major pathologic substrate of dementia but there currently are no validated strategies in the clinical setting to diagnose or treat the disease. HS-Aging affects ~15% of elderly persons and is associated with substantial cognitive impairment. Our group has studied this area extensively, leading to the following major hypothesis: thyroid hormone (TH) dysregulation contributes to HS-Aging pathogenesis. This novel pathogenetic mechanism may provide the basis to diagnose HS- Aging during life using CSF analyses, and to develop a therapeutic strategy. However, critical knowledge gaps remain in terms of characterizing the specific association between TH dysfunction and brain pathology, and the potential to target the mechanism for therapeutic purposes. We propose a research program to fill these knowledge gaps while testing key hypotheses via the following Specific Aims: Hypothesis 1: Clinical TH status is associated with presence and severity of HS-Aging pathology. Specific Aim 1: Test the hypothesis in a convenience sample (n=205, including cognitively intact and diverse non-HS-Aging dementia controls) from the University of Kentucky AD Center biobank. We will apply rigorous, quantitative digital pathologic methods to assess TDP-43 pathology, AD plaques/tangles, and α- synucleinopathy for correlation with clinical TH status: self-reported TH disease and TH medications are well- documented. As expected in aged persons, more than 25% of the subjects exhibited clinical TH dysfunction. Hypothesis 2: CSF TH levels are associated with HS-Aging pathology and may provide a novel biomarker. Specific Aim 2: Evaluate TH (triiodothyronine, or T3) in CSF as a clinical biomarker of HS-Aging. We will assess human CSF TH levels with direct correlation with various subtypes of pathology. We also will test TH in clinical CSF from lumbar punctures, correlated with established AD-related biomarkers (Aβ and tau) and HS-Aging SNPs, with the goal of developing a new method to diagnose HS-Aging in living persons. We have obtained CSF from autopsied individuals (n=104) and clinical CSF samples (n=195) to accomplish this Aim. Hypothesis 3: Specific HS-Aging risk-associated gene variants induce altered brain TH levels with extensive impact on brain gene expression, and orally available drugs can alter this pathogenetic mechanism. Specific Aim 3: Define gene expression changes relevant to TH and HS-Aging. We will analyze human genomics databases to define how gene changes linked to HS-Aging risk contribute to variability in ABCC9 and SLCO1C1 (a major brain TH transporter) expression. We will test human cells (cultured human hESC astrocytes and lymphoblastoid cells transformed with DNA from people with known genotypes and pathology) to determine the potential for manipulating the levels of ABCC9, of TH transporter SLCO1C1, and of other TH- regulated genes. Finally, in mice, we will test how TH-responsive gene expression, neuropathology, and neurobehavior are affected in vivo by treatment with TH and/or the ABCC9 agonist drug glimepiride.

海马衰老硬化（HS-Aging）是痴呆的主要病理基础，但目前有 临床环境中没有经过验证的策略来诊断或治疗该疾病。 HS-老化影响约 15% 老年人，并与严重的认知障碍有关。我们组已经研究过这个领域 广泛，导致以下主要假设：甲状腺激素（TH）失调会导致 HS-老化发病机制。这种新的发病机制可能为HS-的诊断提供依据。 使用脑脊液分析分析生命中的衰老情况，并制定治疗策略。然而，关键知识 在描述 TH 功能障碍和脑病理学之间的具体关联方面仍然存在差距， 以及将该机制用于治疗目的的潜力。我们提出一个研究计划来填补 这些知识差距，同时通过以下具体目标测试关键假设： 假设 1：临床 TH 状态与 HS-Aging 病理的存在和严重程度相关。 具体目标 1：在方便样本中检验假设（n=205，包括认知完整和多样化 非 HS-Aging 痴呆对照）来自肯塔基大学 AD 中心生物库。我们将严格执行， 定量数字病理方法评估 TDP-43 病理学、AD 斑块/缠结和 α- 突触核蛋白病与临床 TH 状态的相关性：自我报告的 TH 疾病和 TH 药物是很好的 记录在案。正如在老年人中所预期的那样，超过 25% 的受试者表现出临床 TH 功能障碍。 假设 2：CSF TH 水平与 HS-Aging 病理学相关，可能提供一种新的生物标志物。 具体目标 2：评估 CSF 中的 TH（三碘甲状腺原氨酸，或 T3）作为 HS-Aging 的临床生物标志物。我们将 评估与各种病理亚型直接相关的人类脑脊液 TH 水平。我们也会测试TH 腰椎穿刺的临床脑脊液中，与已建立的 AD 相关生物标志物（Aβ 和 tau）相关， HS-Aging SNP，目标是开发一种新方法来诊断活人的 HS-Aging。我们有 从尸检个体 (n = 104) 和临床 CSF 样本 (n = 195) 中获取 CSF 以实现这一目标。 假设 3：特定的 HS-Aging 风险相关基因变异会导致大脑 TH 水平发生广泛的改变 对大脑基因表达的影响，口服药物可以改变这种发病机制。 具体目标 3：定义与 TH 和 HS 老化相关的基因表达变化。我们将分析人类 基因组数据库来定义与 HS-Aging 风险相关的基因变化如何导致 ABCC9 的变异 和 SLCO1C1（一种主要的脑 TH 转运蛋白）表达。我们将测试人类细胞（培养的人类 hESC 用已知基因型和病理学人群的 DNA 转化的星形胶质细胞和淋巴母细胞） 确定操纵 ABCC9、TH 转运蛋白 SLCO1C1 和其他 TH- 水平的潜力 调控基因。最后，我们将在小鼠中测试 TH 反应基因表达、神经病理学和 TH 和/或 ABCC9 激动剂药物格列美脲治疗会影响体内神经行为。