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Dominantly Inherited Alzheimer Network: Project 2

显性遗传阿尔茨海默病网络：项目 2

基本信息

批准号：
10665747
负责人：
BRIAN Andrew GORDON
金额：
$ 53.42万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665747
关键词：
Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Precursor Antibodies Autopsy Behavioral Binding Biological Biological Markers Biology Brain Cell Line Cell model Cerebrospinal Fluid Characteristics Clinical Cognitive Collaborations Data Data Collection Dementia Development Disease Disease Marker Disease Progression Elements Evaluation Evolution Family Freezing Funding Genes Genetic Health Heritability Human Immunohistochemistry Impaired cognition Impairment Individual Induced pluripotent stem cell derived neurons Inherited Late Onset Alzheimer Disease Lead Learning Ligand Binding Ligands Liquid substance Location Magnetic Resonance Imaging Maps Mass Spectrum Analysis Measures Metabolism Mutation Nerve Degeneration Neurofibrillary Tangles Neuropsychological Tests Normalcy Observational Study Pathogenesis Pathologic Pathology Phosphorylation Phosphorylation Site Play Population Positron-Emission Tomography Process Property Proteins Quantitative Autoradiography Research Research Personnel Role Sensitivity and Specificity Site Slice Symptoms Techniques Therapeutic Agents Therapeutic Trials Time Tissues Titrations Tracer Uncertainty Work autosomal dominant Alzheimer&apos s disease brain tissue cohort gray matter high risk improved in vivo innovation insight mutation carrier mutational status neuroimaging neuropathology novel novel therapeutics presenilin-1 presenilin-2 progression marker tau Proteins tau aggregation tau-1 therapeutic target

项目摘要

Project 2: Tau SUMMARY Alzheimer's disease (AD) is a growing worldwide health crisis. It is critical to develop biomarkers to identify individuals at high risk for AD, better understand the biological underpinnings of the disease, and to develop new therapeutic agents. Autosomal dominant AD (ADAD) is a rare form of the disease (<1%) that is caused by mutations in one of three genes. Individuals with these mutations develop dementia at a relatively young age that is heritable within families. This provides a unique cohort of individuals where it is possible to predict the disease stage of individuals relative to their estimated years to symptom onset (EYO) even decades before they show cognitive decline. During the initial funding periods DIAN investigators have mapped out a sequential progression of biomarkers; first, measures of beta-amyloid become abnormal, followed by metabolism, measures of tau pathology, loss of grey matter, and eventually cognitive decline. Work by DIAN investigators and others suggests that the abnormal accumulation of tau pathology may be a key factor in this cascade that impacts the transition from cognitive normality to impairment. However, prior work examining tau has previously been limited only to one biomarker measured in the cerebrospinal fluid (CSF). While informative, this solitary measure may not adequately convey the role tau pathology plays in AD. This project seeks to understand new measures of tau pathology in the DIAN cohort to further elucidate the role this protein plays in ADAD. Aim 1 explores tau pathology measured using three different positron emission tomography (PET) compounds to map the spread of tau pathology in the brain. This will quantify the amount as well as location of pathological burden in the brain. Aim 2 uses post mortem brain tissue to validate these tracers and learn more about the sensitivity and specific of these three compounds. This is critical before these PET tracers can be used broadly for research and clinical purposes. Aim 3 uses mass spectrometry to quantify novel forms of tau which have distinct structural properties (e.g. different phosphorylation or cleavage sites). These novel forms of tau will be measured in the CSF, brain tissue, and human cell models of AD and is a strong compliment to the tau PET imaging. The rationale for this proposal is that better understanding the temporal and spatial evolution of tau pathology is critical to understanding the pathobiology of AD and for formulating successful therapeutic trials. These three Aims are highly collaborative with the other Projects and Cores, and will provide new insights in the role tau pathology plays in AD.

项目2:Tau SUMMARY