Extracellular tau oligomers and Alzheimer disease

描述(申请人提供)：tau蛋白聚集形成神经原纤维缠结，β-淀粉样多肽在淀粉样斑块中积聚，以及神经元丢失是阿尔茨海默病的主要组织病理学特征。突触加强过程的损害很可能是该病的早期事件，最终导致严重的认知缺陷。最近的证据表明，细胞外的寡聚体tau蛋白损害了突触功能和记忆。然而，tau寡聚体影响突触机制的研究还很少。通过这一提议，将探索tau寡聚体引起基础神经传递和可塑性变化的分子基础。研究的具体目标如下：1)确定tau寡聚体诱导的突触传递的变化；2)寻找tau寡聚体导致突触功能障碍的潜在机制；3)确定CREB磷酸化上调是否能对抗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、成像和行为技术的组合来实现。这些研究的结果将揭开tau蛋白影响的新机制和分子靶点，可能被用来开发治疗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方法。

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.