Caspase activation precedes and leads to tangles

被引:405
作者
de Calignon, Alix [1 ,2 ]
Fox, Leora M. [1 ]
Pitstick, Rose [3 ]
Carlson, George A. [3 ]
Bacskai, Brian J. [1 ]
Spires-Jones, Tara L. [1 ]
Hyman, Bradley T. [1 ]
机构
[1] Harvard Univ, Alzheimers Dis Res Lab, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Dept Neurol,Med S, Charlestown, MA 02129 USA
[2] Univ Paris 06, F-75005 Paris, France
[3] McLaughlin Res Inst, Great Falls, MT 59401 USA
关键词
MOUSE MODEL; NEUROFIBRILLARY TANGLES; NEURONAL LOSS; TAU-PHOSPHORYLATION; CONGO RED; CLEAVAGE; AGGREGATION; TRUNCATION; DISSOCIATION; EXPRESSION;
D O I
10.1038/nature08890
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Studies of post-mortem tissue have shown that the location of fibrillar tau deposits, called neurofibrillary tangles (NFT), matches closely with regions of massive neuronal death(1,2), severe cytological abnormalities(3), and markers of caspase activation and apoptosis(4-6), leading to the idea that tangles cause neurodegeneration in Alzheimer's disease and tau-related frontotemporal dementia. However, using in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain), we find the opposite: caspase activation occurs first, and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wild-type 4-repeat tau (tau-4R) into wild-type animals triggered caspase activation, tau truncation and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wild-type mice led to the appearance of intracellular aggregates, tangle-related conformational-and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, we propose a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, we suggest that tangles are 'off pathway' to acute neuronal death. Soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration.
引用
收藏
页码:1201 / U123
页数:5
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