Project 2: Neuropathology of Amyloid and Tau

摘要-项目2：淀粉样蛋白和TAU的神经病理学。神经原纤维的存在 内嗅皮层(EC)中的缠结(NFT)是皮质-海马环路的一个结点，它不仅是一个恒定的 阿尔茨海默病(AD)最早病理阶段的特征，但也是几乎普遍存在的发现 临床正常老年人的尸检。可以想象两种截然不同的可能命运：所有 欧共体的港湾NFT(例如，根据Braak和Braak Staging的I-II阶段)不可避免地将展示 Tau病变扩散到其他脑区，并在足够的时间内出现痴呆症症状；或 其中一部分人的大脑具有特定的特征，这使得他们不太容易受到神经毒素的影响 阿尔茨海默病的病理影响，他们将保持无症状。我们将测试一个模型，在该模型中，tau错误本地化到 突触间隔是突触丢失和tau释放的基础，突触是突触的底物 NFT在大脑皮层中传播。新型PHF-tau靶向PET示踪剂的研究进展 T807，量身定做，允许在体内检测NFT和相关的磷酸盐病理，代表了一个独特的 有机会测试这一模型，并阐明如何解释 欧洲委员会中的NFT。本项目的设计目的是：1)验证T807-PET在死后人脑中的有效性 在细胞和分子水平上准确理解T807配体保留意味着什么。具体地说，我们将测试 认为新的T807配体靶向NFT以及异常的神经细胞和突触堆积 过度磷酸化的tau；以及2)识别相关的解剖和生化异常，这些异常可能 区分既有NFT又有突触和神经元缺失的个体，似乎是最早的 AD的不同阶段，来自那些发展为NFT但对神经元、突触和神经胶质反应具有弹性的人 伴随着纠缠在EC中的存在。我们将测试淀粉样蛋白沉积的存在 影响tau在神经突起中的积累，从而影响进程。这个模型的进一步预测是 可溶性寡聚体tau在海马神经元突触中的选择性聚集和错位定位 其他潜在的突触易损性结节，如后扣带回和梭形/下颞回， 与神经系统完整性的丧失有关。重要的是，在EC中NFT的这些分子和细胞相关性 只能在尸检时检查。我们已经开始在MADRC提供的案例中检验这一模式 脑库，并将这样做在哈布斯案例中进行尸检，但意识到案例的特征很好 进行尸检的人可能很少。因此，我们建议利用非常有特色的Rush 队列(基于人群的独立生活个体队列，尸检率接近100%， 纵向临床评估)，以便我们能够确保能够选择与临床相匹配的病例 赤潮受试者的特征。该程序将开发必要的数据来指导对tau的解释 在临床环境中进行神经成像，并为未来有效的治疗干预确定合理的靶点。

SUMMARY—PROJECT 2: NEUROPATHOLOGY OF AMYLOID AND TAU. The presence of neurofibrillary tangles (NFT) in the entorhinal cortex (EC), a nodal point of cortico-hippocampal circuits, is not only a constant feature of the earliest pathological stages of Alzheimer's disease (AD) but also a nearly universal finding at autopsy in clinically normal elders. Two very different possible fates can be imagined: All individuals who harbor NFT in the EC (e.g., Stages I-II according to Braak and Braak staging) are inevitably destined to exhibit spreading of tau pathology to other brain regions and to develop symptoms of dementia given enough time; or a proportion of them have specific features in their brains that render them less vulnerable to the neurotoxic effects of AD pathology, and they will remain asymptomatic. We will test a model in which tau mislocalization to the synaptic compartment underlies synaptic loss, and release of tau at the synapse that is the substrate of NFT propagation across the cortex. The recent development of novel PHF-tau targeting PET tracers, such as T807, tailored to allow in vivo detection of NFT and related phosphotau pathologies, represents a unique opportunity to test this model, and to shed light on the fundamental question of how to interpret the presence of NFT in the EC. This project has been designed to: 1) validate T807-PET in postmortem human brain, to best understand exactly what T807 ligand retention implies at a cellular and molecular level. Specifically, we will test the idea that novel T807 ligand targets NFT as well as abnormal neuritic and synaptic accumulations of hyperphosphorylated tau; and 2) identify associated anatomical and biochemical abnormalities that may differentiate individuals who have both NFT and synaptic and neuronal loss, and appear to be in the earliest stages of AD, from those who develop NFT but are resilient to neuronal, synaptic, and glial responses that can accompany the presence of tangles in the EC. We will test the proposal that the presence of amyloid deposits impacts tau accumulation in neurites and hence in progression. A further prediction of this model is that selective accumulation and mislocalization of soluble oligomeric tau into the synapses in the hippocampus and other potential nodes of synaptic vulnerability, like posterior cingulate and fusiform/inferior temporal gyri, correlate with loss of neural system integrity. Importantly, these molecular and cellular correlates of NFT in EC can be examined only at autopsy. We have begun to examine this model in cases available from the MADRC Brain Bank, and will do so in HABS cases that come to autopsy, but realize that cases of well-characterized controls coming to autopsy may be few. We therefore propose to utilize the very well-characterized Rush cohorts (population based cohorts of independently living individuals with nearly 100% autopsy rates and longitudinal clinical evaluations) so that we are assured of being able to select cases that match the clinical characteristics of HABS subjects. This program will develop the data necessary to guide interpretation of tau neuroimaging in clinical settings and to define rational targets for future effective therapeutic interventions.