Hsp90 chaperone inhibitor 17-AAG Attenuates Aβ-induced synaptic toxicity and memory impairment

Yaomin Chen, Bin Wang, Dan Liu, Jing Jing Li, Yueqiang Xue, Kazuko Sakata, Ling Qiang Zhu, Scott Heldt, Huaxi Xu, Francesca-Fang Liao

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2464-2470
Number of pages7
JournalJournal of Neuroscience
Volume34
Issue number7
DOIs
StatePublished - Feb 14 2014

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tanespimycin
Synapses
Alzheimer Disease
Synapsins
Neurons
Heat-Shock Response
Synaptophysin
Proteins
Neuronal Plasticity
Neuroprotective Agents
Inbred C57BL Mouse
Amyloid
Neurodegenerative Diseases
Transgenic Mice
Fear
Hippocampus

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Hsp90 chaperone inhibitor 17-AAG Attenuates Aβ-induced synaptic toxicity and memory impairment. / Chen, Yaomin; Wang, Bin; Liu, Dan; Li, Jing Jing; Xue, Yueqiang; Sakata, Kazuko; Zhu, Ling Qiang; Heldt, Scott; Xu, Huaxi; Liao, Francesca-Fang.

In: Journal of Neuroscience, Vol. 34, No. 7, 14.02.2014, p. 2464-2470.

Research output: Contribution to journalArticle

Chen, Yaomin ; Wang, Bin ; Liu, Dan ; Li, Jing Jing ; Xue, Yueqiang ; Sakata, Kazuko ; Zhu, Ling Qiang ; Heldt, Scott ; Xu, Huaxi ; Liao, Francesca-Fang. / Hsp90 chaperone inhibitor 17-AAG Attenuates Aβ-induced synaptic toxicity and memory impairment. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 7. pp. 2464-2470.
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