Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to Aβ oligomers accumulation.
Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to Aβ oligomers accumulation.
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DOI：
10.1186/1750-1326-5-51
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发表时间：
2010-11-11
影响因子：
15.1
通讯作者：
Oddo S
中科院分区：
文献类型：
--
作者：
Caccamo A;Magrí A;Oddo S
反式反应DNA结合蛋白43（TDP-43）是在额颞叶变性伴泛素阳性包涵体和肌萎缩侧索硬化中发现的病理蛋白。在患病组织中，TDP-43从其生理核位置易位到细胞质中，并在细胞质中积累。此外，TDP-43的C-末端片段在受影响的脑区域中积累，并且足以在体外引起TDP-43错误定位和细胞质积累。TDP-43也在30%的阿尔茨海默病（AD）病例中积累，这一发现具有高度可重复性。TDP-43在AD中的作用及其与AD的两个神经病理学标志Aβ和tau病理学的关系仍有待阐明。在这里，我们发现TDP-43及其~35 kDa C-末端片段的水平在3×Tg-AD小鼠中显著增加，3 ×Tg-AD小鼠是一种AD动物模型，其发生与Aβ和tau积累相关的年龄依赖性认知衰退。我们还报道了TDP-43及其C-末端片段的水平与可溶性Aβ寡聚体的水平相关，其在AD发病机制中起关键作用。值得注意的是，通过遗传减少Aβ42的产生，可将TDP-43及其约35 kDa C-末端片段的水平恢复至对照水平。这些数据表明Aβ寡聚体与TDP-43之间可能存在相关性。
Transactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In diseased tissue, TDP-43 translocates from its physiological nuclear location into the cytoplasm, where it accumulates. Additionally, C-terminal fragments of TDP-43 accumulate in affected brain regions and are sufficient to cause TDP-43 mislocalization and cytoplasmic accumulation in vitro. TDP-43 also accumulates in 30% of Alzheimer disease (AD) cases, a finding that has been highly reproducible. The role of TDP-43 in AD and its relation with Aβ and tau pathology, the two neuropathological hallmarks of AD, remains to be elucidated. Here we show that levels of TDP-43 and its ~35 kDa C-terminal fragment are significantly increased in the 3×Tg-AD mice, an animal model of AD that develops an age-dependent cognitive decline linked to the accumulation of Aβ and tau. We also report that the levels of TDP-43 and its C-terminal fragment correlate with the levels of soluble Aβ oligomers, which play a key role in AD pathogenesis. Notably, genetically reducing Aβ42 production restores the levels of TDP-43 and its ~35 kDa C-terminal fragment to control levels. These data suggest a possible relation between Aβ oligomers and TDP-43.
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DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
DOI：
10.1073/pnas.85.11.4051
发表时间：
1988-06-01
影响因子：
11.1
作者：
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25
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Oddo, Salvatore
影响因子：
12.7
作者：
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Akiyama, Haruhiko