title: Hsp90 chaperone inhibitor 17-AAG attenuates Aβ-induced synaptic toxicity and memory impairment.
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.
authors: Neurodegenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, Department of Pharmacology and Anatomy & Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163, and Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors: Yaomin
authors: Y
authors: Chen
authors: Bin
authors: B
authors: Wang
authors: Dan
authors: D
authors: Liu
authors: Jing Jing
authors: JJ
authors: Li
authors: Yueqiang
authors: Y
authors: Xue
authors: Kazuko
authors: K
authors: Sakata
authors: Ling-qiang
authors: LQ
authors: Zhu
authors: Scott A
authors: SA
authors: Heldt
authors: Huaxi
authors: H
authors: Xu
authors: Francesca-Fang
authors: FF
authors: Liao
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin