Hsp90 Chaperone Inhibitor 17-AAG Attenuates Aβ-Induced Synaptic Toxicity and Memory Impairment
| Autor: | Ling-Qiang Zhu, Jing Jing Li, Francesca-Fang Liao, Bin Wang, Dan Liu, YueQiang Xue, Kazuko Sakata, Huaxi Xu, Yaomin Chen, Scott A. Heldt |
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| Rok vydání: | 2014 |
| Předmět: |
Synapsin I
Lactams Macrocyclic Blotting Western Long-Term Potentiation Mice Transgenic Biology Neuroprotection Mice Alzheimer Disease Memory Benzoquinones polycyclic compounds Animals HSP90 Heat-Shock Proteins HSF1 Neurons Amyloid beta-Peptides General Neuroscience Long-term potentiation Immunohistochemistry Rats Cell biology Mice Inbred C57BL Disease Models Animal Synaptic fatigue Chaperone (protein) Synapses Synaptic plasticity Synaptophysin biology.protein Brief Communications Neuroscience |
| Zdroj: | The Journal of Neuroscience. 34:2464-2470 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.0151-13.2014 |
| Popis: | The excessive accumulation of soluble amyloid peptides (Aβ) plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in synaptic dysfunction. The role of the two major chaperone proteins, Hsp70 and Hsp90, in clearing misfolded protein aggregates has been established. Despite their abundant presence in synapses, the role of these chaperones in synapses remains elusive. Here, we report that Hsp90 inhibition by 17-AAG elicited not only a heat shock-like response but also upregulated presynaptic and postsynaptic proteins, such as synapsin I, synaptophysin, and PSD95 in neurons. 17-AAG treatment enhanced high-frequency stimulation-evoked LTP and protected neurons from synaptic damage induced by soluble Aβ. In AD transgenic mice, the daily administration of 17-AAG over 7 d resulted in a marked increase in PSD95 expression in hippocampi. 17-AAG treatments in wild-type C57BL/6 mice challenged by soluble Aβ significantly improved contextual fear memory. Further, we demonstrate that 17-AAG activated synaptic protein expression via transcriptional mechanisms through the heat shock transcription factor HSF1. Together, our findings identify a novel function of Hsp90 inhibition in regulating synaptic plasticity, in addition to the known neuroprotective effects of the chaperones against Aβ and tau toxicity, thus further supporting the potential of Hsp90 inhibitors in treating neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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