Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism.
Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism.
复制标题
DOI：
10.1016/j.jbc.2021.100715
复制
发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Strickland DK
中科院分区：
文献类型：
--
作者：
Cooper JM;Lathuiliere A;Migliorini M;Arai AL;Wani MM;Dujardin S;Muratoglu SC;Hyman BT;Strickland DK
在阿尔茨海默病(AD)中，病理形式的tau在细胞间转移和胞浆tau的“种子”聚集。Tau的磷酸化在神经退行性tau病中起着关键作用。此外，载脂蛋白E(ApoE)是大脑中脂蛋白的主要组成部分，也是AD的遗传风险决定因素。载脂蛋白E受体，低密度脂蛋白受体相关蛋白1(LRP1)，作为tau的内吞受体，对tau在tau疾病中的作用提出了几个问题：内化的tau是否像其他LRP1配体一样被运送到溶酶体进行降解，以及LRP1是否内化了病理性tau导致胞质播种？我们发现LRP1迅速内化125I标记的tau，然后在溶酶体中有效降解。表面等离子体共振实验证实了tau和tau微管结合域与LRP1的高亲和力结合。有趣的是，磷酸化形式的重组tau与LRP1结合较弱，并不能有效地被LRP1内化。ApoE抑制LRP1介导的tau摄取，apoE4亚型是最有效的抑制剂，可能是因为它与LRP1有更高的亲和力。利用来自人类AD脑组织裂解产物的翻译后修饰的tau，我们发现表达LRP1的细胞，而不是LRP1缺陷的细胞，在apoE增强的过程中促进胞浆tau的播种。这些研究确定LRP1是一种内吞受体，它结合和处理单体形式的tau，导致其降解，并通过病理形式的tau促进播种。这些过程的平衡可能是阿尔茨海默病患者神经病理学在整个大脑中传播的基础。
In Alzheimer's disease (AD), pathological forms of tau are transferred from cell to cell and “seed” aggregation of cytoplasmic tau. Phosphorylation of tau plays a key role in neurodegenerative tauopathies. In addition, apolipoprotein E (apoE), a major component of lipoproteins in the brain, is a genetic risk determinant for AD. The identification of the apoE receptor, low-density lipoprotein receptor–related protein 1 (LRP1), as an endocytic receptor for tau raises several questions about the role of LRP1 in tauopathies: is internalized tau, like other LRP1 ligands, delivered to lysosomes for degradation, and does LRP1 internalize pathological tau leading to cytosolic seeding? We found that LRP1 rapidly internalizes 125I-labeled tau, which is then efficiently degraded in lysosomal compartments. Surface plasmon resonance experiments confirm high affinity binding of tau and the tau microtubule-binding domain to LRP1. Interestingly, phosphorylated forms of recombinant tau bind weakly to LRP1 and are less efficiently internalized by LRP1. LRP1-mediated uptake of tau is inhibited by apoE, with the apoE4 isoform being the most potent inhibitor, likely because of its higher affinity for LRP1. Employing post-translationally–modified tau derived from brain lysates of human AD brain tissue, we found that LRP1-expressing cells, but not LRP1-deficient cells, promote cytosolic tau seeding in a process enhanced by apoE. These studies identify LRP1 as an endocytic receptor that binds and processes monomeric forms of tau leading to its degradation and promotes seeding by pathological forms of tau. The balance of these processes may be fundamental to the spread of neuropathology across the brain in AD.
登录
查看更多内容
影响因子：
4.3
作者：
DeVos SL;Corjuc BT;Oakley DH;Nobuhara CK;Bannon RN;Chase A;Commins C;Gonzalez JA;Dooley PM;Frosch MP;Hyman BT
通讯作者：
Hyman BT
DOI：
10.1073/pnas.82.10.3197
发表时间：
1985-01-01
影响因子：
11.1
作者：
ESKO, JD;STEWART, TE;TAYLOR, WH
通讯作者：
TAYLOR, WH
影响因子：
1.2
作者：
Furman, Jennifer L.;Holmes, Brandon B.;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
影响因子：
16
作者：
Fisher, C;Beglova, N;Blacklow, SC
通讯作者：
Blacklow, SC
影响因子：
16.2
作者：
BRAMBLETT, GT;GOEDERT, M;LEE, VMY
通讯作者：
LEE, VMY