Subgroups of Alzheimer Disease

阿尔茨海默病的亚组

• 批准号: 7803578
• 负责人: KHALID IQBAL
• 金额: $ 32.98万
• 依托单位: INSTITUTE FOR BASIC RES IN DEV DISABIL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803578
• 关键词: Alzheimer' s Disease; Animal Model; Antibodies; Apolipoprotein E; Area; Autopsy; Biological Assay; Biological Markers; Brain; Cessation of life; Classification; Clinical; Cluster Analysis; Cytosol; Data; Dementia; Diagnosis; Diagnostic; Disease; Dot Immunoblotting; Down Syndrome; Enzyme-Linked Immunosorbent Assay; Freezing; Frequencies; Frontotemporal Dementia; Future; Generations; Genotype; Hallucinations; Heterogeneity; Hypokinesia; Immunoassay; In Vitro; Investigation; Knowledge; Lead; Lesion; Literature; Measurement; Measures; Mental Depression; Methodology; Molecular; Monitor; Monoclonal Antibodies; Morus; Muscle Rigidity; Nature; Neocortex; Neurofibrillary Tangles; Neurologic; Oryctolagus cuniculus; Outcome; Outcome Measure; Particulate; Pathology; Patients; Pattern; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Phosphorylation Site; Phosphotransferases; Procedures; Process; Protein Kinase; Proteins; Radio; Reaction; Recycling; Reporter; Research; Research Personnel; Senile Plaques; Sensitivity and Specificity; Serine; Signal Pathway; Site; Specificity; Staging; Subgroup; Symptoms; Tauopathies; Testing; Threonine; Transgenic Mice; Treatment Efficacy; Ubiquitin; Work; abnormally phosphorylated tau; base; case-based; disorder control; disorder subtype; improved; in vivo; molecular marker; mouse model; programs; self assembly; tau Proteins; tau aggregation; tau phosphorylation; tau-1

DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate the nature of different signaling pathways involved in the etiopathogenesis of neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark brain lesion of Alzheimer disease (AD), Down syndrome, frontotemporal dementia, and other tauopathies, and employ this information to identify and diagnose the different subgroups of Alzheimer's disease. We postulate that more than one disease mechanism and signaling pathway are involved in producing AD pathology, and that various subgroups of this disease can be identified based on CSF levels of proteins associated with plaques and neurofibrillary tangles and of taus abnormally phosphorylated at various specific sites. To test this hypothesis we propose (1) to develop and validate ultrasensitive bienzyme-recycle ELISAs for various abnormal phosphorylation sites of tau. (2) To determine CSF levels of A¿, ubiquitin and total tau, and tau phosphorylated at various specific sites using the assays developed in Aim #1 in AD and control cases, and identify subgroups of AD based on these data by cluster analysis. APOE genotype frequencies and clinical profiles of each cluster, including symptoms such as depression, hallucinations, hypokinesia, and rigidity, will be analyzed. The % sensitivity and % specificity of each phosphorylation site at appropriate cut-off points will be determined to evaluate its diagnostic potential. (3) To study the relationship of levels of soluble and aggregated A¿1, 2, ubiquitin and various phosphotaus between CSF and brain in Alzheimer's disease. Levels of soluble and aggregated A¿2, ubiquitin and various phosphotaus will be assayed by ELISA and radioimmuno-dot-blots in the frozen autopsied brains of AD cases from which lumbar CSFs are available. The levels of these markers in the brain will be correlated to the histopathological staging of the disease, and to the CSF levels of these markers. These studies will help (i) identify subgroups of AD based on CSF markers, (ii) provide a lead on the nature of signaling pathways involved in various subgroups, (iii) reveal the diagnostic potential of CSF levels of tau phosphorylated at different specific sites and (iv) identify the relationship of the CSF levels of A¿, ubiquitin and tau to these markers in the brain and to the various histopathological stages of Alzheimer's disease. Better classification of AD at the molecular level and identification of biomarkers that represent the underlying disease process of various subtypes of the disease, in the long term, will lead to improved diagnosis and better defined treatment opportunities for AD and other tauopathies.

描述（由申请人提供）：本提案的总体目标是研究参与异常过度磷酸化 tau 神经原纤维变性发病机制的不同信号通路的性质，异常过度磷酸化 tau 是阿尔茨海默病 (AD)、唐氏综合症、额颞叶痴呆的标志性脑损伤和其他 tau蛋白病，并利用这些信息来识别和诊断阿尔茨海默氏病的不同亚型，我们假设涉及不止一种疾病机制和信号通路。产生 AD 病理学的过程中，并且可以根据脑脊液中斑块和神经原纤维缠结相关蛋白以及在各个特定位点异常磷酸化的 taus 的水平来识别该疾病的各个亚组。为了检验这一假设，我们建议 (1) 开发和验证。针对 tau 的各种异常磷酸化位点的超灵敏双酶回收 ELISA (2) 测定 A¿ 的 CSF 水平。使用目标 #1 中开发的检测方法在 AD 和对照病例中检测不同特定位点的泛素和总 tau 蛋白，并通过聚类分析根据这些数据识别 AD 亚组，APOE 基因型频率和临床特征。包括诸如抑郁、幻觉、运动机能减退和强直等症状，将确定每个磷酸化位点在适当截止点的％敏感性和％特异性以进行评估。 (3) 研究可溶性A和聚集性A水平之间的关系1、2、阿尔茨海默氏病脑脊液和大脑之间的泛素和各种磷酸盐的可溶性和聚集性 A¿ 2、将通过ELISA和放射免疫斑点印迹在可获得腰椎CSF的AD病例的冷冻尸检大脑中测定泛素和各种磷酸化物。大脑中这些标记物的水平将与疾病的组织病理学分期相关。以及这些标记物的 CSF 水平，这些研究将有助于 (i) 根据 CSF 标记物识别 AD 亚组，(ii) 为信号通路的性质提供线索。涉及各个亚组，(iii) 揭示不同特定位点磷酸化的 CSF 水平的诊断潜力，以及 (iv) 确定 A¿ 的 CSF 水平之间的关系从长远来看，将 、 泛素和 tau 蛋白与大脑中的这些标记物以及阿尔茨海默氏病的各个组织病理学阶段相结合，在分子水平上更好地对 AD 进行分类，并识别代表该疾病各种亚型的潜在疾病过程的生物标记物。将改善AD和其他tau蛋白病的诊断并更好地确定治疗机会。