Induction of heat-shock proteins (HSPs), such as via Hsp90 inhibition of heart shock protein 90 (Hsp90), is being investigated as a treatment option for neurodegenerative diseases such as Alzheimer's disease (AD). This is believed to be mediated primarily via activated heat-shock transcription factor/HSF1, a major eukaryotic stress-responsive factor that is expressed in most cell systems and protects cells from cell death. Recently, we administered a CNS-permeable Hsp90 inhibitor (NXD) in cultured neurons and mice, and found that this upregulated not only HSPs (iHSp70, Hsp40, Hsp27, etc.), but also several pre- and post-synaptic protein genes (e.g., synapsin, synaptophysin, PSD95, BDNF) at transcriptional levels. We found that this inhibitor completely rescued synapses from the detrimental effects of soluble A in C57BL/6 mice, preventing deterioration in hippocampus-dependent contextual fear conditioning. Notably, when a specific HSF1 inhibitor (KRIBB11) was co-administered with A and NXD to mouse brain, it completely abolished NXD's effect. Furthermore, chronic treatment of early symptomatic Tg2576 mice (9-12 MO) with systemic NXD completely rescued the spatial memory deficit, as determined by various maze tests, accompanied by increased iHsp70 as well as PSD95 and BDNF proteins in treated mice. Most interestingly, NXD treatment induced rapid and sustained HSF1 heat shock-like response, as evidenced by nuclear translocation (active state) and induced iHsp70 expression, which was most prominently expressed in the pyramidal neurons of hippocampal CA1, as compared to distal CA3 or neocortex. Together, our findings strongly suggest an important role of HSF1 in synaptic plasticity; to date, its neuronal functions remained largely unknown. We hypothesize that HSF1 is a key regulator of synaptic transcriptome, and regulates a large number of genes crucial and related to synaptic functions; NXD's protective effect on synapses is largely mediated via HSF1-dependent mechanisms. Since the NXD compound represents a good candidate for future development of new AD therapeutic strategies, we aim to investigate in-depth mechanisms underlying its protective effects, with special focus on HSF-1 dependent transcription. Accordingly, three specific aims are to test several hypotheses that 1) HSF1 plays a crucial role in AD and transcriptionally active HSF1 is required for Hsp90 inhibitor's effects in mice, 2) HSF1 can globally modulate the synaptic transcriptome related to synaptic plasticity (LCM/RNA-seq) of CA1/CA3 dendrites), and 3) chronically activated HSF1 works equivalently as Hsp90 inhibitor in rescuing AD mice. Successful outcomes from this study will likely validate HSF1 as a therapeutic target for synaptic and memory disorders.

Public Health Relevance

We aim to validate the newly identified roles of druggable Hsp90 inhibitor in regulating synaptic functions in several acute and chronic mouse model of AD. Successful validation of its multiple beneficial effects may identify a potential therapeutic agent useful in preventing and treating AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG049772-05
Application #
9700474
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2015-05-01
Project End
2020-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38103
Li, Jing Jing; Wang, Bin; Kodali, Mahesh Chandra et al. (2018) In vivo evidence for the contribution of peripheral circulating inflammatory exosomes to neuroinflammation. J Neuroinflammation 15:8
Wang, B; Liu, Y; Huang, L et al. (2017) A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism. Mol Psychiatry 22:990-1001
Kim, Eunhee; Sakata, Kazuko; Liao, Francesca-Fang (2017) Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation. PLoS Genet 13:e1006849
Li, Jing Jing; Wang, Ruishan; Lama, Rati et al. (2016) Ubiquitin Ligase NEDD4 Regulates PPAR? Stability and Adipocyte Differentiation in 3T3-L1 Cells. Sci Rep 6:38550
Kim, Eunhee; Wang, Bin; Sastry, Namratha et al. (2016) NEDD4-mediated HSF1 degradation underlies ?-synucleinopathy. Hum Mol Genet 25:211-22
Wang, Ruishan; Chen, Shaoya; Liu, Yingchun et al. (2015) All-trans-retinoic acid reduces BACE1 expression under inflammatory conditions via modulation of nuclear factor ?B (NF?B) signaling. J Biol Chem 290:22532-42