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Extracellular tau oligomers and Alzheimer disease

细胞外 tau 寡聚体与阿尔茨海默病

基本信息

批准号：
9130081
负责人：
OTTAVIO ARANCIO
金额：
$ 32.8万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130081
关键词：
Action Potentials Address Affect Affinity Alzheimer&apos s Disease Amyloid beta-Protein Antibodies Axonal Transport Behavioral Binding Biochemical Brain Cell Culture Techniques Cell physiology Cerebrospinal Fluid Chemosensitization Clinical Cognitive deficits Cyclic AMP-Responsive DNA-Binding Protein Cyclic GMP Disease Docking Electrophysiology (science)Epitopes Event Exposure to Extracellular Space Fatigue Functional disorder Future Glutamates Health Hippocampus (Brain)Human Image Immunotherapy Impaired cognition Impairment Individual Intercellular Fluid Laboratories Lead Learning Long-Term Potentiation Memory Memory Loss Microtubule Stabilization Mining Mitochondria Molecular Molecular Target Neurites Neurofibrillary Tangles Neurons Pathology Pathway interactions Patients Phosphorylation Physiologic pulse Physiological Play Preparation Process Proteins Recombinants Senile Plaques Site Slice Specificity Specimen Structure Symptoms Synapses Synapsin I Synaptic Transmission Synaptic plasticity Synaptophysin Techniques Therapeutic Up-Regulation Vesicle analog base brain cell conformer density dimer drug discovery extracellular hippocampal pyramidal neuron immunoreactivity inhibitor/antagonist mouse model neurofibrillary tangle formation neuron loss neurotransmission neurotransmitter release phosphodiesterase V postsynaptic presynaptic receptor research study response synaptic function tau Proteins tau aggregation tau dysfunction tau function tau mutation therapeutic development transmission process vesicular release

项目摘要

DESCRIPTION (provided by applicant): Aggregation of tau protein to form neurofibrillary tangles together with accumulation of beta-amyloid peptides in amyloid plaques, and neuronal loss are major histopathological hallmarks of Alzheimer's disease. Impairment of processes involved in synaptic strengthening is likely to constitute an early event in the disease that eventually leads to severe cognitive deficits. Recent evidence suggests that extracellular oligomeric tau protein impairs synaptic function and memory. However, synaptic mechanisms affected by tau oligomers have been very poorly explored. With this proposal, the molecular basis of tau oligomer-induced changes in basal neurotransmission and plasticity will be explored. The following specific aims will be tackled: 1) to identify changes of synaptic transmission induced by tau oligomers; 2) to search for potential mechanisms of synaptic dysfunction by tau oligomers; 3) to determine if up-regulation of CREB phosphorylation counteracts tau-induced synaptic dysfunction and memory loss. These aims will be addressed through a combination of electrophysiological, biochemical, imaging and behavioral techniques. Findings derived from these studies will unravel new mechanisms and molecular targets affected by tau protein that might be exploited for developing a treatment against Alzheimer's disease and other disorders characterized by cognitive impairment and abnormal tau pathology.

描述（由申请人提供）：tau蛋白聚集形成神经原纤维缠结，淀粉样斑块中β -淀粉样肽积累，神经元丢失是阿尔茨海默病的主要组织病理学标志。参与突触强化过程的损伤可能构成该疾病的早期事件，最终导致严重的认知缺陷。最近的证据表明，细胞外寡聚tau蛋白损害突触功能和记忆。然而，tau寡聚物影响突触机制的研究很少。在此基础上，探讨tau寡聚物诱导的基础神经传递和可塑性变化的分子基础。以下具体目标将解决：1)确定tau低聚物诱导的突触传递的变化；2)通过tau低聚物寻找突触功能障碍的潜在机制；3)确定CREB磷酸化的上调是否抵消tau诱导的突触功能障碍和记忆丧失。这些目标将通过电生理、生化、成像和行为技术的结合来解决。这些研究的发现将揭示受tau蛋白影响的新机制和分子靶点，可能用于开发针对阿尔茨海默病和其他以认知障碍和异常tau病理为特征的疾病的治疗。