Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer's disease.
Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer's disease.
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DOI：
10.1186/s40478-018-0567-4
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发表时间：
2018-07-13
影响因子：
7.1
通讯作者：
Bolognin S
中科院分区：
文献类型：
--
作者：
Borin M;Saraceno C;Catania M;Lorenzetto E;Pontelli V;Paterlini A;Fostinelli S;Avesani A;Di Fede G;Zanusso G;Benussi L;Binetti G;Zorzan S;Ghidoni R;Buffelli M;Bolognin S
阿尔茨海默病（AD）最早的病理特征之一是树突棘的丧失。在可能介导这种神经元连接丧失的许多因素中，Rho-GTP酶的贡献特别令人感兴趣。这个蛋白质家族多年来一直被认为是肌动蛋白细胞骨架重塑的关键调节因子。最近的研究表明，在病理条件下，它的复杂信号也可能被触发。在这里，我们发现，与非痴呆对照组相比，AD患者额叶皮层中Rho-GTdR家族成员Rac 1水平降低。此外，与年龄匹配的非痴呆对照组相比，简易精神状态检查< 18的AD患者的血浆样本中Rac 1增加。使用不同的组成型活性肽使我们能够在体外研究Rac 1特异性信号。它的活化增加了淀粉样前体蛋白的加工，并诱导SET从细胞核易位到细胞质，导致tau蛋白在pT 181残基处过度磷酸化。值得注意的是，Rac 1在6周龄3xTg-AD小鼠的海马中异常激活。然而，总蛋白水平在7个月时下降。基于在6.5个月时鼻内施用Rac 1活性肽的拯救策略防止了树突棘丢失。这些数据表明，根据病理学的不同阶段，Rac 1可能具有双重作用。在初始阶段，Rac 1失调可能是由于对Aβ和tau的直接影响而引起的触发辅因子。然而，在病理学的后期阶段，由于对脊柱动力学的有益作用，它可能代表潜在的治疗靶点。本文的在线版本（10.1186/s40478-018-0567-4）包含补充材料，可供授权用户使用。
One of the earliest pathological features characterizing Alzheimer’s disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling. More recent insights have indicated how its complex signaling might be triggered also in pathological conditions. Here, we showed that the Rho-GTPase family member Rac1 levels decreased in the frontal cortex of AD patients compared to non-demented controls. Also, Rac1 increased in plasma samples of AD patients with Mini-Mental State Examination < 18 compared to age-matched non demented controls. The use of different constitutively active peptides allowed us to investigate in vitro Rac1 specific signaling. Its activation increased the processing of amyloid precursor protein and induced the translocation of SET from the nucleus to the cytoplasm, resulting in tau hyperphosphorylation at residue pT181. Notably, Rac1 was abnormally activated in the hippocampus of 6-week-old 3xTg-AD mice. However, the total protein levels decreased at 7-months. A rescue strategy based on the intranasal administration of Rac1 active peptide at 6.5 months prevented dendritic spine loss. This data suggests the intriguing possibility of a dual role of Rac1 according to the different stages of the pathology. In an initial stage, Rac1 deregulation might represent a triggering co-factor due to the direct effect on Aβ and tau. However, at a later stage of the pathology, it might represent a potential therapeutic target due to the beneficial effect on spine dynamics. The online version of this article (10.1186/s40478-018-0567-4) contains supplementary material, which is available to authorized users.
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影响因子：
4
作者：
Ghosh, Suman;Shinogle, Heather E.;Garg, Gaurav;Vielhauer, George A.;Holzbeierlein, Jeffrey M.;Dobrowsky, Rick T.;Blagg, Brian S. J.
通讯作者：
Blagg, Brian S. J.
树突稳定性的分子机制。
影响因子：
34.7
作者：
Koleske, Anthony J.
通讯作者：
Koleske, Anthony J.
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J
影响因子：
--
作者：
Bamburg, James R.;Bloom, George S.
通讯作者：
Bloom, George S.
影响因子：
6
作者：
Falke, E;Nissanov, J;Arnold, SE
通讯作者：
Arnold, SE