- 作者：Jose Abisambra ; Umesh K. Jinwal ; Yoshinari Miyata ; Justin Rogers ; Laura Blair ; Xiaokai Li ; S ; lin P. Seguin ; Li Wang ; Ying Jin ; Justin Bacon ; Sarah Brady ; Matthew Cockman ; Chantal Guidi ; Juan Zhang ; John Koren ; Zapporah T. Young ; Christopher A. Atkins ; Bo Zhang ; Lisa Y. Lawson ; Edwin J. Weeber ; et al.
- 关键词：Alzheimer&rsquo ; s disease ; chaperones ; Hsc70 ; rhodacyanine ; tau ; YM-01
- 刊名：Biological Psychiatry
- 出版年：2013
- 出版时间：1 September, 2013
- 年：2013
- 卷：74
- 期：5
- 页码：367-374
- 全文大小：1228 K
Background
The microtubule-associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer¡¯s disease. 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.Methods
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 heat shock protein 70 (Hsp70) family in the brain, heat shock cognate 70 protein (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.
Results
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, overexpression of heat shock protein 40 (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, wild-type 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 tau transgenic brain slices.
Conclusions
Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in Alzheimer¡¯s disease and other tauopathies.