Subgroups of Alzheimer Disease

阿尔茨海默病的亚组

• 批准号: 7251582
• 负责人: KHALID IQBAL
• 金额: $ 32.8万
• 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/7251582
• 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; Condition; 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; Range; Reaction; Recycling; Reporter; Research; Research Personnel; Senile Plaques; Sensitivity and Specificity; Serine; Signal Pathway; Site; Specificity; Staging; Subgroup; Symptoms; Tauopathies; Testing; Threonine; Transgenic Organisms; Treatment Efficacy; Ubiquitin; Work; abnormally phosphorylated tau; base; case-based; concept; disorder control; disorder subtype; improved; in vivo; 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高磷酸化tau（阿尔茨海默病（AD）、唐氏综合征、额颞叶痴呆和其他tau病的标志性脑损伤）神经原纤维变性发病机制的不同信号通路的性质，并利用这些信息来识别和诊断阿尔茨海默病的不同亚群。我们假设，多种疾病机制和信号通路参与了AD病理的产生，并且基于脑脊液中与斑块和神经原纤维缠结相关的蛋白质水平以及在不同特定部位异常磷酸化的tau蛋白水平，可以确定该疾病的不同亚群。为了验证这一假设，我们提出(1)开发并验证针对tau蛋白各种异常磷酸化位点的超灵敏双酶循环elisa。(2)利用Aim #1中开发的检测方法测定AD和对照病例脑脊液中A¿、泛素和总tau蛋白的水平，以及不同特定位点磷酸化的tau蛋白水平，并根据这些数据通过聚类分析确定AD的亚组。将分析APOE基因型频率和每个群集的临床概况，包括抑郁、幻觉、运动障碍和僵硬等症状。将确定每个磷酸化位点在适当截断点的%敏感性和%特异性，以评估其诊断潜力。(3)研究阿尔茨海默病患者脑脊液与脑间可溶性和聚集性A¿1、2、泛素及各种磷水平的关系。通过ELISA和放射免疫斑点斑点法检测AD患者冷冻尸检脑组织中可溶性和聚集性A¿2、泛素和各种磷的水平。大脑中这些标记物的水平将与疾病的组织病理学分期以及脑脊液中这些标记物的水平相关。这些研究将有助于(i)根据脑脊液标记物确定AD的亚组，（ii）为不同亚组中涉及的信号通路的性质提供线索，（iii）揭示脑脊液中不同特定位点磷酸化的tau水平的诊断潜力，以及（iv）确定脑脊液中a¿、泛素和tau水平与大脑中这些标记物和阿尔茨海默病不同组织病理阶段的关系。从长远来看，在分子水平上更好地对阿尔茨海默病进行分类，并识别代表该疾病各种亚型潜在疾病过程的生物标志物，将提高阿尔茨海默病和其他牛头病变的诊断水平，并提供更好的治疗机会。