Mechanisms of Cell-to-Cell Transmission of Pathological Tau: A Review.
Mechanisms of Cell-to-Cell Transmission of Pathological Tau: A Review.
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DOI：
10.1001/jamaneurol.2018.2505
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发表时间：
2019-01-01
期刊：
影响因子：
29
通讯作者：
Trojanowski JQ
中科院分区：
文献类型：
--
作者：
Gibbons GS;Lee VMY;Trojanowski JQ
细胞内tau蛋白聚集体是神经退行性tau蛋白病的病理学标志，包括阿尔茨海默病（AD）、进行性核上性麻痹（PSP）、皮质基底节变性（CBD）和皮克病。新出现的证据支持蛋白质性病理性tau种子的细胞间传递模型，其导致内源性细胞tau的募集和模板化纤维化，随后异常tau在整个脑中扩散。这些发现导致了应变假说，该假说预测tau的不同构象应变或多晶型物可能是tau蛋白病的临床和神经病理学异质性和细胞类型特异性的基础。在这篇综述中，我们描述了不同的tau蛋白株在细胞培养和AD动物模型中繁殖的证据，以及病理性tau蛋白在细胞间传播的机制。将合成的tau预形成的原纤维和人脑源性病理性tau颅内注射到非转基因野生型小鼠和表达β-淀粉样蛋白和tau-淀粉样蛋白沉积的AD转基因小鼠模型中，在远离注射部位的神经解剖学连接的脑区域中观察到广泛的病理性tau聚集体。此外，当将从不同的tau蛋白病（即患有AD、PSP和CBD的脑）获得的人脑来源的病理性tau蛋白注射到野生型小鼠的脑中时，它们接种了tau蛋白病，并忠实地重现了每种tau蛋白病的细胞类型特异性tau蛋白包涵体特征，其呈时间依赖性、剂量依赖性和注射部位依赖性扩散，反映了注射部位的连接体。这些发现提供了令人信服的证据，即tau蛋白的错误折叠或病理构象以tau蛋白病菌株特异性方式进行细胞间扩散。重要的是，迄今为止的证据支持病理性tau菌株的行为不像感染因子，尽管越来越多的证据表明这些tau菌株经历模板化繁殖和传播，与注射部位的神经解剖学连接体相关。
Intracellular tau protein aggregates are a pathological hallmark of neurodegenerative tauopathies, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease. Emerging evidence supports a model of cell-to-cell transmission of proteinaceous pathological tau seeds, which leads to recruitment and templated fibrillization of endogenous cellular tau followed by the spread of abnormal tau throughout the brain. These findings lead to the strain hypothesis, which predicts that distinct conformational strains or polymorphs of tau may underlie the clinical and neuropathological heterogeneity and cell-type specificity of tauopathies. In this review, we describe the evidence for propagation of distinct tau strains in cell culture and animal models of AD and mechanistic insights into cell-to-cell transmission of pathological tau. Intracranial injections of synthetic tau-preformed fibrils and human brain-derived pathological tau into nontransgenic wild-type mice and transgenic mouse models of AD expressing β-amyloid and tau-amyloid deposits yield widespread pathological tau aggregates observed in neuroanatomically connected brain regions distant from the site of injection. Furthermore, when human brain–derived pathological tau obtained from distinct tauopathies (ie, brains with AD, PSP, and CBD) were injected into the brains of wild-type mice, they seeded tau pathology and faithfully recapitulated cell-type specific tau inclusions characteristic of each tauopathy in a time-dependent, dose-dependent, and injection site–dependent spread reflective of the connectome of the injection site. These findings provide compelling evidence that misfolded or pathological conformers of tau undergo cell-to-cell spread in a tauopathy strain-specific manner. Importantly, evidence to date supports that pathological tau strains do not behave like infectious agents, despite growing evidence that these tau strains undergo templated propagation and spread linked to the neuroanatomical connectome of the injection site.
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影响因子：
5.3
作者：
Gibbons, Garrett S.;Banks, Rachel A.;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.
DOI：
10.3233/jpd-150691
发表时间：
2016
期刊：
Journal of Parkinson's disease
影响因子：
--
作者：
Bousset L;Brundin P;Böckmann A;Meier B;Melki R
通讯作者：
Melki R
DOI：
10.1083/jcb.101.4.1371
发表时间：
1985-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Binder LI;Frankfurter A;Rebhun LI
通讯作者：
Rebhun LI
影响因子：
5.3
作者：
Castillo-Carranza, Diana L.;Sengupta, Urmi;Kayed, Rakez
通讯作者：
Kayed, Rakez
影响因子：
16.6
作者：
Ambadipudi S;Biernat J;Riedel D;Mandelkow E;Zweckstetter M
通讯作者：
Zweckstetter M