Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer's mouse model.
Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer's mouse model.
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DOI：
10.1007/s00401-016-1637-y
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发表时间：
2016-12
影响因子：
12.7
通讯作者：
Wong PC
中科院分区：
文献类型：
--
作者：
LaClair KD;Donde A;Ling JP;Jeong YH;Chhabra R;Martin LJ;Wong PC
TDP-43蛋白质病最初与ALS和FTD相关，在30-60%的阿尔茨海默病（AD）病例中也发现了TDP-43蛋白质病，并与认知恶化和神经变性相关。这种蛋白质病的一个主要组成部分是这种RNA结合蛋白从细胞核中的耗竭，这损害了神经退行性疾病中非保守的隐蔽外显子的抑制。为了测试TDP-43的核耗竭是否可能有助于具有TDP-43蛋白质病的AD病例的发病机制，我们检查了TDP-43耗竭在AD中脆弱的神经元群体中的影响，以及在AD相关背景下对神经变性的影响。在这里，我们表明，一些在AD中选择性易感的锥体神经元群体也容易受到小鼠中TDP-43耗尽的影响，而其他前脑神经元似乎幸免于难。此外，AD小鼠模型前脑神经元中的TDP-43耗竭加剧了神经变性，并与前原纤维寡聚体Aβ增加和Aβ斑块负荷降低相关。这些发现支持TDP-43的核耗竭在AD发病机制中的作用，并为开发新的治疗方法以减轻TDP-43和与其核丢失相关的功能性生前生物标志物的耗竭提供了强有力的理论基础。
TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30–60% of Alzheimer's disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric Aβ and decreased Aβ plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.
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影响因子：
16.2
作者：
Kim, Jungsu;Basak, Jacob M.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
15.1
作者：
Kayed R;Head E;Sarsoza F;Saing T;Cotman CW;Necula M;Margol L;Wu J;Breydo L;Thompson JL;Rasool S;Gurlo T;Butler P;Glabe CG
通讯作者：
Glabe CG
影响因子：
14.5
作者：
Andrade-Moraes, Carlos Humberto;Oliveira-Pinto, Ana V.;Lent, Roberto
通讯作者：
Lent, Roberto
细胞死亡的基本与附件方面：NCCD 2015的建议。
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
3.7
作者：
Frisch S;Dukart J;Vogt B;Horstmann A;Becker G;Villringer A;Barthel H;Sabri O;Müller K;Schroeter ML
通讯作者：
Schroeter ML