Seeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like Tangles

被引:467
作者
Guo, Jing L.
Lee, Virginia M. -Y.
机构
[1] Univ Penn, Sch Med, Dept Pathol & Lab Med, Inst Aging, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
MICROTUBULE-ASSOCIATED PROTEIN; PAIRED HELICAL FILAMENTS; BLOOD-BRAIN-BARRIER; FTDP-17 MISSENSE MUTATIONS; FIBRILLIZATION IN-VITRO; FRONTOTEMPORAL DEMENTIA; NEUROFIBRILLARY TANGLES; P301L TAU; ADSORPTIVE ENDOCYTOSIS; ALPHA-SYNUCLEIN;
D O I
10.1074/jbc.M110.209296
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neurofibrillary tangles (NFTs) in Alzheimer disease and related tauopathies are composed of insoluble hyperphosphorylated Tau protein, but the mechanisms underlying the conversion of highly soluble Tau into insoluble NFTs remain elusive. Here, we demonstrate that introduction of minute quantities of misfolded preformed Tau fibrils (Tau pffs) into Tau-expressing cells rapidly recruit large amounts of soluble Tau into filamentous inclusions resembling NFTs with unprecedented efficiency, suggesting a "seeding"-recruitment process as a highly plausible mechanism underlying NFT formation in vivo. Consistent with the emerging concept of prion-like transmissibility of disease-causing amyloidogenic proteins, we found that spontaneous uptake of Tau pffs into cells is likely mediated by endocytosis, suggesting a potential mechanism for the propagation of Tau lesions in tauopathy brains. Furthermore, sequestration of soluble Tau by pff-induced Tau aggregates attenuates microtubule overstabilization in Tau-expressing cells, supporting the hypothesis of a Tau loss-of-function toxicity in cells harboring NFTs. In summary, our study establishes a cellular system that robustly develops authentic NFT-like Tau aggregates, which provides mechanistic insights into NFT pathogenesis and a potential tool for identifying Tau-based therapeutics.
引用
收藏
页码:15317 / 15331
页数:15
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