Project 2: Neuropathology of Amyloid and Tau

总结-项目2：淀粉样蛋白和TAU的神经病理学。神经系统的存在 内嗅皮层（EC）是皮层-海马神经回路的节点，其神经纤维缠结（NFT）不仅是一个常数， 阿尔茨海默病（AD）的最早病理阶段的特征，但也是一个几乎普遍的发现， 临床正常老年人的尸检。可以想象两种截然不同的命运： EC中的NFT（例如，阶段I-II根据Braak和Braak分期）不可避免地注定要展出 tau病变扩散到其他脑区，并在足够的时间内出现痴呆症状;或 他们中的一部分人在大脑中有特殊的特征，使他们不太容易受到神经毒素的影响。 AD病理学的影响，他们将保持无症状。我们将测试一个模型，其中tau蛋白错误定位， 突触区室是突触丢失的基础，而突触处的tau释放是突触的底物。 NFT在皮层的传播。最近开发的新型PHF-tau靶向PET示踪剂，如 T807被定制为允许体内检测NFT和相关的磷酸化tau病理，代表了独特的 有机会测试这个模型，并阐明如何解释的存在的基本问题， NFT在EC。本项目旨在：1）验证T807-PET在死后人脑中的作用，以最佳 确切地理解T807配体保留在细胞和分子水平上意味着什么。具体来说，我们将测试 新的T807配体靶向NFT以及异常的神经炎和突触积累的想法， 过度磷酸化的tau;和2）鉴定相关的解剖学和生物化学异常， 区分那些既有NFT又有突触和神经元损失的个体， AD阶段，从那些发展NFT但对神经元，突触和神经胶质反应有弹性的人， 伴随着EC中缠结的存在。我们将检验淀粉样蛋白沉积物的存在 影响神经突中的tau积累并因此影响进展。该模型的进一步预测是， 可溶性寡聚tau在海马中的突触中的选择性积累和错误定位， 其他潜在的突触脆弱节点，如后扣带回和梭状/颞下回， 与神经系统完整性的丧失有关重要的是，EC中NFT的这些分子和细胞相关物 只有在尸检时才能检查。我们已经开始在MADRC提供的案例中检查此模型 脑银行，并会这样做，在HABS的情况下，来验尸，但认识到，案件的特点 尸检的控制可能很少。因此，我们建议利用非常好的特点拉什 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），以便我们能够确保选择与临床评估相匹配的病例。 HABS主题的特点。该计划将开发必要的数据来指导对tau的解释。 在临床环境中的神经影像学，并确定合理的目标，为未来有效的治疗干预。

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.