Department of Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Mol Neurodegener. 2010 Nov 11;5:51. doi: 10.1186/1750-1326-5-51.
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.
转译激活反应 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性侧索硬化症中发现的病理蛋白。在病变组织中，TDP-43 从其生理核位置易位到细胞质中，在细胞质中积累。此外，TDP-43 的 C 末端片段在受影响的大脑区域中积累，并且足以导致 TDP-43 体外定位错误和细胞质积累。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 Aβ 和 tau 病理学的关系，即 AD 的两个神经病理学标志，仍有待阐明。
我们在这里表明，在 3×Tg-AD 小鼠中，TDP-43 及其35 kDa C 末端片段的水平显著增加，3×Tg-AD 是一种 AD 动物模型，其认知能力随 Aβ 和 tau 的积累而呈年龄依赖性下降。我们还报告说，TDP-43 及其 C 末端片段的水平与可溶性 Aβ 寡聚物的水平相关，可溶性 Aβ 寡聚物在 AD 发病机制中起关键作用。值得注意的是，遗传降低 Aβ42 的产生可将 TDP-43 及其35 kDa C 末端片段的水平恢复至对照水平。
这些数据表明 Aβ 寡聚物和 TDP-43 之间可能存在关系。
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