Tau seeding and strains in the clinicopathologic heterogeneity of Alzheimer disease

项目摘要/摘要 阿尔茨海默病(AD)可以通过不同的方式影响患者。它通常表现为递进记忆 导致痴呆症的失落。然而，AD可以有非典型的表现，当其他认知领域 更显著的影响，如语言、视觉空间或执行功能。阿尔茨海默病患者也可能 有路易体痴呆(DLB)的症状，如帕金森症、视觉障碍 幻觉、认知波动或做梦行为。在这些情况下，很难预测 病理学。在尸检中，阿尔茨海默病的诊断是通过发现由淀粉样蛋白和神经原纤维组成的老年斑 用牛磺酸制成的缠结。由α-突触核蛋白组成的路易小体(Lb)在DLb中被发现，但也很常见 在公元后。混合病理被认为与较差的结果有关。我们不知道是什么原因导致了临床 变异性以及混合病理如何影响临床综合征。这些知识差距使人们很难 预测疾病进程，这对治疗患者和开发新的AD治疗方法具有重要意义。 在阿尔茨海默病中，在整个大脑中异常扩散和积累的蛋白tau可能是一个关键因素。这个 假说是，tau像蛋白一样在蛋白病中传播，在这种疾病中，异常的tau“菌株”容易 积聚从一个细胞传播到另一个细胞，将天然tau转化为异常菌株。这就是“种子”的进一步积累。 和异常tau的扩散。有许多类型的tau菌株，每种类型都有不同的特性，包括它们如何 积累以及它们传播的速度。我们的工作假设是不同的tau菌株可以解释 阿尔茨海默病临床表现的变异性以及某些tau株与α-突触核蛋白相互作用影响临床 综合症。我们将通过研究德克萨斯大学西南部的尸检样本来检验这些假设 阿尔茨海默氏症中心。戴蒙德博士的实验室将鉴定tau菌株并分段测量tau种子 从使用他们的新型生物传感器细胞线板的选定案例中。目标1将比较tau菌株在慢性阻塞性肺疾病患者中的作用 典型和非典型的陈述。这里的tau菌株鉴定将确定菌株是否与 特殊的临床表现。Aim 2将通过选择具有以下特征的病例来研究tau和α-突触核蛋白的相互作用 AD、LB或混合病理。病例将通过临床综合征(AD或DLB)以及这是否 匹配的病理(例如，临床AD与仅AD的病理)、具有混合的病理或具有不匹配的(例如 临床AD高LB病理)。Tau种子和品系类型将与tau和α-突触核蛋白进行比较 基于病理和临床诊断的不同脑区和分组之间的病理学。我们 怀疑某些tau菌株增加了α-突触核蛋白的播种，并与DLB有关 综合症。该项目在AD发病机制方面的研究进展将 提高我们预测疾病进程的能力，完善正在开发和新发疾病的研究工作- 修改治疗方法。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) can affect patients in different ways. It typically presents with progressive memory loss that leads to dementia. However, AD can have atypical presentations when other areas of cognition are affected more prominently, such as language, visuospatial or executive functioning. Patients with AD may also have symptoms that are indicative of dementia with Lewy bodies (DLB), such as parkinsonism, visual hallucinations, cognitive fluctuations or dream enactment behavior. In these cases, it is difficult to predict the pathology. At autopsy, AD is diagnosed by findings of senile plaques made of amyloid and neurofibrillary tangles made of tau. Lewy bodies (LB), made of α-synuclein, are found in DLB, but are also commonly found in AD. Mixed pathology has been linked to poorer outcomes. We do not know what causes the clinical variability nor how mixed pathology affects the clinical syndrome. These knowledge gaps make it difficult to predict disease course, which has implications when treating patients and developing new treatments for AD. Protein tau, which spreads and accumulates abnormally throughout the brain in AD, may be a key factor. The hypothesis is that tau spreads like proteins in prion disease, where an abnormal tau “strain” that is prone to buildup spreads from cell to cell to convert native tau to the abnormal strain. This then “seeds” further buildup and spread of abnormal tau. There are many tau strain types, each with distinct properties including how they accumulate and how fast they spread. Our working hypotheses are that different tau strains account for the variability in AD presentations and that certain tau strains interact with α-synuclein to affect the clinical syndrome. We will test these hypotheses by studying autopsy specimens from the UT Southwestern Alzheimer’s Disease Center. Dr. Diamond’s lab will identify tau strains and measuring tau seeding in sections from selected cases using their novel biosensor cell line panel. Aim 1 will compare tau strains in cases with typical and atypical presentations. Tau strain identifications here will determine if strains are associated with a particular clinical presentation. Aim 2 will study tau and α-synuclein interactions by selecting cases that have AD, LB, or mixed pathology. Cases will be defined by clinical syndrome (AD or DLB) and whether this matched pathology (e.g. clinical AD with AD-only pathology), had mixed pathology, or had a mismatch (e.g. clinical AD high LB pathology). Tau seeding and strain types will be compared to the tau and α-synuclein pathology in different brain regions and between groupings based on pathology and clinical diagnoses. We suspect that certain tau strains have increased seeding with α-synuclein and are associated with a DLB syndrome. The advancements in understanding disease mechanisms of AD resulting from this project will improve our abilities to predict disease course and refine research efforts in developing and new disease- modifying therapies.