Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau.
Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau.
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DOI：
10.1016/j.biopsych.2013.02.027
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发表时间：
2013-09-01
影响因子：
10.6
通讯作者：
Dickey, Chad A.
中科院分区：
文献类型：
--
作者：
Abisambra, Jose;Jinwal, Umesh K.;Miyata, Yoshinari;Rogers, Justin;Blair, Laura;Li, Xiaokai;Seguin, Sandlin P.;Wang, Li;Jin, Ying;Bacon, Justin;Brady, Sarah;Cockman, Matthew;Guidi, Chantal;Zhang, Juan;Koren, John;Young, Zapporah T.;Atkins, Christopher A.;Zhang, Bo;Lawson, Lisa Y.;Weeber, Edwin J.;Brodsky, Jeffrey L.;Gestwicki, Jason E.;Dickey, Chad A.
微管相关蛋白tau在神经退行性疾病中积聚，这种疾病被称为tauopathies，最常见的是阿尔茨海默病(AD)。治疗这些疾病的一种方法可能是通过伴侣操作降低异常的tau水平，从而颠覆由tau的有毒积累引起的突触可塑性缺陷。采用肌松模型研究YM-01对tau的影响。YM-01是大脑中含量最丰富的Hsp70家族变体Hsc70的分流功能的变构启动子。通过生化方法、细胞培养和原代培养tau转基因小鼠神经元，对YM-01修饰Hsc70活性和tau稳定性的机制进行了研究。将YM-01应用于tau小鼠的急性脑片，检测tau稳定性的变化和学习记忆的电生理相关性。经纳米分子浓度的YM-01处理后，在体外和体外，tau水平迅速和有效地降低。与Hsc70在这一过程中起关键作用的情况一致，Hsp40(DNAJB2)的过表达抑制了YM-01的活性。与其在致病性tau病模型中的作用相比，YM-01在正常、野生型小鼠的体外脑片中几乎没有活性，除非微管被破坏，这表明Hsc70优先作用于异常的游离tau池。最后，YM-01处理增加了tau转基因脑片的长期增强作用。利用伴侣蛋白选择性靶向异常tau的治疗方法可以迅速而有效地挽救AD和其他tau疾病中发生的突触功能障碍。
The microtubule associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer’s disease (AD). One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau’s toxic accretion. Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the Hsp70 family in the brain, Hsc70. The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured. Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, over-expression of Hsp40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wildtype mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in from tau transgenic brain slices. Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in AD and other tauopathies.
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影响因子：
3.3
作者：
Dawson, H. N.;Cantillana, V.;Jansen, M.;Wang, H.;Vitek, M. P.;Wilcock, D. M.;Lynch, J. R.;Laskowitz, D. T.
通讯作者：
Laskowitz, D. T.
影响因子：
4.8
作者：
Jinwal, Umesh K.;Akoury, Elias;Dickey, Chad A.
通讯作者：
Dickey, Chad A.
影响因子：
3.5
作者：
Chiang, Annette N.;Valderramos, Juan-Carlos;Balachandran, Raghavan;Chovatiya, Raj J.;Mead, Brian P.;Schneider, Corinne;Bell, Samantha L.;Klein, Michael G.;Huryn, Donna M.;Chen, Xiaojiang S.;Day, Billy W.;Fidock, David A.;Wipf, Peter;Brodsky, Jeffrey L.
通讯作者：
Brodsky, Jeffrey L.
DOI：
10.1073/pnas.1201209109
发表时间：
2012-08-21
影响因子：
11.1
作者：
Ardiles, Alvaro O.;Tapia-Rojas, Cheril C.;Palacios, Adrian G.
通讯作者：
Palacios, Adrian G.
影响因子：
5.6
作者：
Abisambra, Jose F.;Jinwal, Umesh K.;Suntharalingam, Amirthaa;Arulselvam, Karthik;Brady, Sarah;Cockman, Matthew;Jin, Ying;Zhang, Bo;Dickey, Chad A.
通讯作者：
Dickey, Chad A.