Subgroups of Alzheimer Disease

阿尔茨海默病的亚组

• 批准号: 8063476
• 负责人: KHALID IQBAL
• 金额: $ 32.09万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063476
• 关键词: Alzheimer' s Disease; Animal Model; Antibodies; Area; Autopsy; Biological Assay; Biological Markers; Brain; Cell model; 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; 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)：这项建议的总体目标是调查异常过度磷酸化tau的神经纤维变性的不同信号通路的性质，tau异常过度磷酸化是阿尔茨海默病(AD)、唐氏综合症、额颞痴呆和其他tauopathy的标志性脑损害，并利用这些信息来识别和诊断阿尔茨海默病的不同亚型。我们推测，多种疾病机制和信号通路参与了AD病理的发生，并且根据脑脊液中与斑块和神经原纤维缠结相关的蛋白以及不同特定部位异常磷酸化的taus的水平，可以识别该疾病的不同亚型。为了验证这一假设，我们建议(1)开发和验证针对tau各种异常磷酸化位点的超灵敏的双酶循环ELISA。(2)用AIM#1中建立的方法测定AD患者和对照患者脑脊液中Aβ、泛素和总tau的水平以及不同部位的tau蛋白的磷酸化水平，并根据这些数据通过聚类分析确定AD的亚型。将分析每个群体的APOE基因频率和临床特征，包括抑郁、幻觉、运动减少和僵硬等症状。每个磷酸化位点在适当的截断点的敏感度和特异度将被确定，以评估其诊断潜力。(3)探讨阿尔茨海默病患者脑脊液和脑组织中可溶性和聚集性A_(1、2)、泛素及各种磷酸盐水平的关系。用酶联免疫吸附试验和放射免疫斑点印迹法检测有腰椎CSF的AD患者冰冻尸脑中可溶性和聚集态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分期相关，并与这些标记物的脑脊液水平相关。这些研究将有助于(I)基于脑脊液标志物确定AD亚型，(Ii)提供与不同亚型有关的信号通路的性质的线索，(Iii)揭示不同特定部位脑脊液中磷酸化的tau水平的诊断潜力，以及(Iv)确定脑脊液中Aβ、泛素和tau的水平与脑内这些标志物以及阿尔茨海默病的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，并识别代表该疾病不同亚型潜在疾病过程的生物标记物，将有助于改善对阿尔茨海默病和其他疾病的诊断和更明确的治疗机会。

项目成果

Novel therapeutic strategies for neurodegenerative disease.

• DOI: 10.1111/j.1479-8301.2009.00289.x
• 发表时间: 2009-06
• 期刊: Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society
• 作者: Tanimukai H;Kudo T;Tanaka T;Grundke-Iqbal I;Iqbal K;Takeda M
• 通讯作者: Takeda M

CSF phospho-tau correlates with behavioural decline and brain insoluble phospho-tau levels in a rat model of tauopathy.

在 tau 病大鼠模型中，CSF 磷酸 tau 与行为下降和脑不溶性磷酸 tau 水平相关。

• DOI: 10.1007/s00401-010-0680-3
• 发表时间: 2010
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Zilka,Norbert;Korenova,Miroslava;Kovacech,Branislav;Iqbal,Khalid;Novak,Michal
• 通讯作者: Novak,Michal