The Role of Beta-Amyloid Assembly States in Tau Pathology and Cognitive Decline

描述（由申请人提供）：阿尔茨海默病（AD）的病理特征是β -淀粉样蛋白（A¿）斑块和含有tau的神经原纤维缠结。最近的证据表明，A¿和tau的可溶性形式都可以影响认知，A¿已被证明可以调节tau病理。然而，介导这些影响的A¿物种在很大程度上仍未得到解决。北极A¿突变（E22G）最近被证明可以增强可溶性A¿原纤维的形成并导致早发性家族性AD，这为A¿聚集状态对AD的发展至关重要提供了强有力的遗传证据。在本提案中，我们将利用北极突变来验证可溶性A¿组装诱导tau病理和认知功能障碍的假设。为了便于我的调查和极大地促进我的职业发展，我将接受Frank LaFerla博士的指导，进行转基因AD模型的设计、生成和分析。此外，Dr. James McGaugh和Dr. Charles Glabe将分别为我提供行为分析和寡聚蛋白生物化学方面的培训。在Aim 1中，我们将利用Arctic A¿突变开发具有年龄依赖性和进进性神经病理学的新型AD转基因模型，以验证可溶性A¿组装体促进野生型hTau的tau病理的假设。我们预计该模型将在不使用突变tau的情况下发展A¿和tau病理，从而更接近地代表AD的病因。在目标2中，我们将评估认知表型及其与A¿和tau病理的相关性。可溶性北极A¿抑制海马LTP的效力是野生型A¿的100倍。因此，我们假设北极突变将通过增强可溶性A¿组装的产生和调节tau病理的发展而迅速产生认知功能障碍。在James McGaugh博士的指导下，我将通过在我们的新型转基因模型中进行认知功能的横断面分析来验证这一假设，并确定认知缺陷是否与病理进展相关。在Aim 3中，我们将检验可溶性A¿组装诱导tau病理和介导认知衰退的假设。为此，Charles Glabe博士将提供寡聚蛋白生物化学方面的指导，他的构象依赖性抗体将用于验证这一假设。结合提出的目标，试图确定可溶性A¿组装是否在tau病理和认知功能障碍的发展中发挥关键作用。

DESCRIPTION (provided by applicant): Alzheimer disease (AD) pathology is characterized by beta-amyloid (A¿) plaques and tau-containing neurofibrillary tangles. Recent evidence suggests that soluble forms of both A¿ and tau can influence cognition and A¿ has been shown to modulate tau pathology. However, the A¿ species that mediates these effects remains largely unresolved. The Arctic A¿ mutation (E22G) has recently been shown to enhance soluble A¿ protofibril formation and cause early-onset familial AD, providing strong genetic evidence that A¿ aggregation state is critical to the development of AD. In this proposal, we will utilize the Arctic mutation to test the hypothesis that soluble A¿ assemblies induce tau pathology and cognitive dysfunction. To facilitate my investigation and greatly enhance my career development, I will receive mentorship from Dr. Frank LaFerla in the design, generation and analysis of transgenic AD models. In addition, Dr. James McGaugh and Dr. Charles Glabe will provide me with training in behavioral analyses and oligomeric protein biochemistry respectively. In Aim 1, we will utilize the Arctic A¿ mutation to develop novel transgenic models of AD with age-dependent and progressive neuropathology to test the hypothesis that soluble A¿ assemblies promote tau pathology from wild type hTau. We anticipate that this model will develop A¿ and tau pathologies without the use of mutant tau, thereby more closely representing the etiology of AD. In Aim 2, we will assess cognitive phenotype and correlations with A¿ and tau pathology. Soluble Arctic A¿ inhibits hippocampal LTP 100-fold more potently than wild-type A¿. Therefore, we hypothesize that the Arctic mutation will rapidly produce cognitive dysfunction via enhancing the generation of soluble A¿ assemblies and modulating the development of tau pathology. Under the guidance of Dr. James McGaugh, I will test this hypothesis by performing a cross-sectional analysis of cognitive function in our novel transgenic models and determine whether cognitive deficits correlate with pathological progression. In Aim 3 we will test the hypothesis that soluble A¿ assemblies induce tau pathology and mediate cognitive decline. In this aim, Dr. Charles Glabe will provide guidance on oligomeric protein biochemistry and his conformational-dependent antibodies will be utilized to test this hypothesis. Combined the proposed aims seek to determine whether soluble A¿ assemblies play a key role in the development of tau pathology and cognitive dysfunction.