TY - JOUR
T1 - STX, a novel membrane estrogen receptor ligand, protects against amyloid-β toxicity
AU - Gray, Nora E.
AU - Zweig, Jonathan A.
AU - Kawamoto, Colleen
AU - Quinn, Joseph F.
AU - Copenhaver, Philip F.
N1 - Funding Information:
Thisworkwas funded by a Department of Veterans Affairs Merit Review grant awarded to J. Quinn, and by NIH grants NS078363 and AG025525 awarded to P. Copenhaver. The authors thank Dr. Martin Kelly for providing his expertise and the STX used in this study, and Dr. Gary Banker and Ms. Barbara Smoody for their support of our experiments with primary hippocampal neurons. We also wish to thank Ms. Jenna Fisk for her assistance with image acquisition in some of our studies. Dr. Doris Kretzschmar provided critical input on this manuscript. We gratefully acknowledge Dr. Stefanie Kaech and Ms. Aurelie Snyder for their invaluable assistance with the confocal imaging analysis that was performed in the Advanced Light Microscopy Core, Jungers Center, OHSU. Confocal imaging was supported in part by NIH P30 NS061800, and by the OHSU School of Medicine Faculty Innovation Fund (to P. Copenhaver). MC65 cells were generously provided by Randy Woltjer, MD, PhD.
Publisher Copyright:
© 2016 IOS Press and the authors.
PY - 2016/3/15
Y1 - 2016/3/15
N2 - Because STX is a selective ligand for membrane estrogen receptors, it may be able to confer the beneficial effects of estrogen without eliciting the deleterious side effects associated with activation of the nuclear estrogen receptors. This study evaluates the neuroprotective properties of STX in the context of amyloid-β (Aβ) exposure. MC65 and SH-SY5Y neuroblastoma cell lines, as well as primary hippocampal neurons from wild type (WT) and Tg2576 mice, were used to investigate the ability of STX to attenuate cell death, mitochondrial dysfunction, dendritic simplification, and synaptic loss induced by Aβ. STX prevented Aβ-induced cell death in both neuroblastoma cell lines; it also normalized the decrease in ATP and mitochondrial gene expression caused by Aβ in these cells. Notably, STX also increased ATP content and mitochondrial gene expression in control neuroblastoma cells (in the absence of Aβ). Likewise in primary neurons, STX increased ATP levels and mitochondrial gene expression in both genotypes. In addition, STX treatment enhanced dendritic arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites caused by Aβ exposure in Tg2576 neurons. These data suggest that STX can act as an effective neuroprotective agent in the context of Aβ toxicity, improving mitochondrial function as well as dendritic growth and synaptic differentiation. In addition, since STX also improved these endpoints in the absence of Aβ, this compound may have broader therapeutic value beyond Alzheimer's disease.
AB - Because STX is a selective ligand for membrane estrogen receptors, it may be able to confer the beneficial effects of estrogen without eliciting the deleterious side effects associated with activation of the nuclear estrogen receptors. This study evaluates the neuroprotective properties of STX in the context of amyloid-β (Aβ) exposure. MC65 and SH-SY5Y neuroblastoma cell lines, as well as primary hippocampal neurons from wild type (WT) and Tg2576 mice, were used to investigate the ability of STX to attenuate cell death, mitochondrial dysfunction, dendritic simplification, and synaptic loss induced by Aβ. STX prevented Aβ-induced cell death in both neuroblastoma cell lines; it also normalized the decrease in ATP and mitochondrial gene expression caused by Aβ in these cells. Notably, STX also increased ATP content and mitochondrial gene expression in control neuroblastoma cells (in the absence of Aβ). Likewise in primary neurons, STX increased ATP levels and mitochondrial gene expression in both genotypes. In addition, STX treatment enhanced dendritic arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites caused by Aβ exposure in Tg2576 neurons. These data suggest that STX can act as an effective neuroprotective agent in the context of Aβ toxicity, improving mitochondrial function as well as dendritic growth and synaptic differentiation. In addition, since STX also improved these endpoints in the absence of Aβ, this compound may have broader therapeutic value beyond Alzheimer's disease.
KW - Amyloid-β toxicity
KW - mitochondrial dysfunction
KW - neuroprotection
KW - selective estrogen receptor modulator
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U2 - 10.3233/JAD-150756
DO - 10.3233/JAD-150756
M3 - Article
C2 - 26890746
AN - SCOPUS:84961773048
SN - 1387-2877
VL - 51
SP - 391
EP - 403
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 2
ER -