TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury.
TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury.
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DOI：
10.1007/s00401-022-02449-w
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发表时间：
2022-08
影响因子：
12.7
通讯作者：
Chen, Chu
中科院分区：
文献类型：
--
作者：
Gao, Fei;Hu, Mei;Zhang, Jian;Hashem, Jack;Chen, Chu
关键词：
创伤性脑损伤已被公认为阿尔茨海默病的重要危险因素。然而，TBI促进AD发生的分子机制尚不清楚。在这里，我们提供的证据表明，TDP-43的异常产生是促进轻度闭合性脑损伤(CHI)小鼠模型AD神经病理以及突触和认知恶化的关键因素。我们观察到，单次轻度CHI足以加重APP转基因小鼠的AD神经病理并加速突触和认知的恶化，但需要重复轻度CHI才能在野生型动物中诱导神经病理改变和突触可塑性、空间学习和记忆保持方面的损害。重要的是，在暴露于单一或重复轻度CHI的动物中，这些变化可以通过沉默TDP-43来缓解，但通过挽救TDP-43基因敲除来恢复。此外，TDP-43在海马区的过度表达加剧了AD的神经病理，并引发了APP转基因小鼠的认知障碍，类似于单一轻微的CHI诱导的变化。我们进一步发现，颅脑损伤引发的神经炎症促进了核因子-TdP B介导的κ-43的转录和表达，进而刺激Tau的磷酸化和Aβ的形成。我们的研究结果表明，TDP-43的过度产生在加重AD神经病理和推动脑损伤后突触和认知功能下降方面发挥了重要作用。
Traumatic brain injury (TBI) has been recognized as an important risk factor for Alzheimer’s disease (AD). However, the molecular mechanisms by which TBI contributes to developing AD remain unclear. Here, we provide evidence that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). We observed that a single mild CHI is sufficient to exacerbate AD neuropathology and accelerate synaptic and cognitive deterioration in APP transgenic mice but repeated mild CHI are required to induce neuropathological changes and impairments in synaptic plasticity, spatial learning, and memory retention in wild-type animals. Importantly, these changes in animals exposed to a single or repeated mild CHI are alleviated by silencing of TDP-43 but reverted by rescue of the TDP-43 knockdown. Moreover, overexpression of TDP-43 in the hippocampus aggravates AD neuropathology and provokes cognitive impairment in APP transgenic mice, mimicking single mild CHI-induced changes. We further discovered that neuroinflammation triggered by TBI promotes NF-κB-mediated transcription and expression of TDP-43, which in turn stimulates tau phosphorylation and Aβ formation. Our findings suggest that excessive production of TDP-43 plays an important role in exacerbating AD neuropathology and in driving synaptic and cognitive declines following TBI.
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影响因子：
5.1
作者：
Hashem J;Hu M;Zhang J;Gao F;Chen C
通讯作者：
Chen C
影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
通讯作者：
Rossoll W
DOI：
10.1136/jnnp-2020-322983
发表时间：
2020-11-11
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
de Boer EMJ;Orie VK;Williams T;Baker MR;De Oliveira HM;Polvikoski T;Silsby M;Menon P;van den Bos M;Halliday GM;van den Berg LH;Van Den Bosch L;van Damme P;Kiernan MC;van Es MA;Vucic S
通讯作者：
Vucic S
影响因子：
3.3
作者：
al-Dahhak, Roula;Khoury, Rita;Grossberg, George T.
通讯作者：
Grossberg, George T.
影响因子：
81.5
作者：
Blennow, Kaj;Brody, David L.;Zetterberg, Henrik
通讯作者：
Zetterberg, Henrik