LRP1-tau interactions and Alzheimer Disease

神经原纤维缠结(NFT)是阿尔茨海默病(AD)神经病理的特征之一。 它们主要由高度磷酸化的微管相关蛋白tau(MAPT)组成， 从轴突错误地定位到细胞质，并聚集在复杂、致密的−褶皱片层中 冷冻电子显微镜测定的成对螺旋细丝(PHF)。神经营养因子在脑内的分布 在AD病例中是压倒性一致的：NFT最初发生在内嗅皮层，然后扩散到 其他边缘和关联区超过十年；这种扩散与临床症状相对应 并与神经元丢失相关。人们很早就认识到，这种传播模式在很大程度上 遵循神经解剖学的联系，并证明了至少部分原因可能是 可以通过错误折叠的tau跨突触元素的传播来解释。最近，人们发现， 低密度脂蛋白受体相关蛋白结合tau并参与tau的增殖。《海曼与斯特里克兰》 自1993年以来，实验室一直在LRP1相关项目上合作，并合作确认这些项目 观察。使用从AD患者脑中分离出的组分，我们证实了LRP1表达细胞，但不是 LRP1缺陷细胞，促进tau播种，表明LRP1介导的摄取可以导致tau逃逸 蛋白质异常的种子进入细胞质。这种情况如何发生的机制(S)目前尚不清楚，将会 在这笔赠款的目标1和3中接受调查。我们还发现了一些残留的吸收，我们现在显示 部分原因是SORL1，另一种与贩运有关的载脂蛋白E受体，而且--重要的是--也明显 与阿尔茨海默病的遗传学有关。SORL1在tau吸收和加工中的作用将在AIMS 2中进行研究 和3)。这些数据和新的问题使我们提出了一个多PI应用程序来探索以下目标： (1)确定LRP1促进tau蛋白病理性播种的机制；(2)确定 SORL1和SORL1突变体到tau蛋白病态种子；(3)确定负责 内生体逃逸与tau种子

Neurofibrillary tangles (NFTs) are one of the characteristic features of Alzheimer disease (AD) neuropathology. They are made primarily of the microtubule associated protein tau (MAPT) that is highly phosphorylated, mislocalized to the cytoplasm from the axon, and aggregated in a complex, dense −pleated sheet that are paired helical filaments (PHFs) as determined by cryo-electron microscopy. The distribution of NFTs in the brain is overwhelmingly consistent across cases of AD: NFT occur initially in the entorhinal cortex, then “spread” to other limbic and association areas over more than a decade; this spread corresponds to the clinical symptoms of the disease, and correlates with neuronal loss. It was recognized early on that the pattern of spread largely followed neuroanatomical connections, and it was demonstrated that at least part of the reason for this could be explained by propagation of misfolded tau across synaptic elements. Recently, it has been discovered that the LDL receptor-related protein binds tau and participates in tau propagation. The Hyman and Strickland laboratories have worked together on LRP1 related projects since 1993 and have collaborated to confirm these observations. Using fractions isolated from AD patient brains, we confirm that LRP1-expressing cells, but not LRP1-deficient cells, promote tau seeding, demonstrating that LRP1 mediated uptake can lead to escape of tau proteopathic seeds into the cytoplasm. The mechanism(s) of how this occurs are currently not known and will be investigated in Aims 1 and 3 of this grant. We also identified some residual uptake that we now show to be due, in part, to SORL1, another apoE receptor that is implicated in trafficking, and – importantly- is also clearly implicated in the genetics of AD. The role of SORL1 in tau uptake and processing will be examined in Aims 2 and 3). These data and new questions lead us to propose a multi-PI application to explore the following aims: (1) Identify mechanisms by which LRP1 promotes proteopathic seeding of tau; (2) Define the contribution of SORL1 and SORL1 mutants to tau proteopathic seeding; (3) Identify mechanisms responsible for the endolysosomal escape and tau seeding