Tau seeding and strains in the clinicopathologic heterogeneity of Alzheimer disease

项目概要/摘要 阿尔茨海默病（AD）可以以不同的方式影响患者。它通常表现为渐进记忆 导致痴呆的损失。然而，当其他认知领域被 影响更突出，如语言，视觉空间或执行功能。AD患者也可能 具有指示路易体痴呆（DLB）的症状，例如帕金森综合征、视觉障碍、 幻觉认知波动或梦境行为在这些情况下，很难预测 病理尸检时，AD的诊断是通过发现由淀粉样蛋白和神经胶质形成的老年斑来进行的。 由tau组成的缠结。路易体（LB），由α-突触核蛋白组成，在DLB中发现，但也常见于 在AD中。混合病理学与较差的结局有关。我们不知道是什么原因导致临床 变异性，也没有混合病理学如何影响临床综合征。这些知识差距使我们很难 预测疾病进程，这对治疗患者和开发AD新疗法具有重要意义。 在AD中在整个大脑中异常扩散和积累的tau蛋白可能是一个关键因素。的 一种假说是tau蛋白像朊病毒疾病中的蛋白质一样传播，在朊病毒疾病中， 积聚从细胞扩散到细胞以将天然tau转化为异常应变。然后，这“种子”进一步积累 以及异常tau蛋白的扩散有许多tau菌株类型，每一种都具有不同的特性，包括它们如何 积累和传播的速度。我们的工作假设是，不同的tau蛋白株解释了 AD表现的变异性和某些tau菌株与α-突触核蛋白相互作用， 综合征我们将通过研究来自UT西南部的尸检标本来验证这些假设。 阿尔茨海默病中心戴蒙德博士的实验室将识别tau菌株，并在切片中测量tau种子。 使用他们的新型生物传感器细胞系面板。目的1将比较Tau菌株在患有 典型和非典型的介绍。这里的Tau菌株鉴定将确定菌株是否与 特殊的临床表现。目标2将通过选择具有以下特征的病例来研究tau蛋白和α-突触核蛋白的相互作用： AD、LB或混合病理。病例将根据临床综合征（AD或DLB）定义， 匹配的病理学（例如，临床AD与仅AD病理学）、具有混合病理学或具有不匹配（例如， 临床AD高LB病理学）。将Tau接种和菌株类型与tau和α-突触核蛋白进行比较 基于病理学和临床诊断，在不同脑区域和分组之间进行病理学研究。我们 怀疑某些tau菌株增加了α-突触核蛋白的接种，并与DLB相关， 综合征该项目在了解AD疾病机制方面的进展将 提高我们预测疾病进程的能力，并改进发展中和新疾病的研究工作- 改良疗法

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.