title: STX, a Novel Membrane Estrogen Receptor Ligand, Protects Against Amyloid-β Toxicity.
abstract: 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.
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Nora E
authors.initials: NE
authors.lastname: Gray
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Zweig
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Kawamoto
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, OR, USA.|Department of Neurology and Parkinson's Disease Research Education and Clinical Care Center (PADRECC), Portland Veterans Affairs Medical Center, Portland, OR, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Copenhaver
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D050259:Genes, Mitochondrial / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: C553231:2-(4-hydroxyphenyl)-3-phenylpent-2-enoic acid (4-(2-dimethylaminoethoxy)phenyl)amide; D000178:Acrylamides; D016229:Amyloid beta-Peptides; D020847:Estrogen Receptor Modulators; D018696:Neuroprotective Agents; D000255:Adenosine Triphosphate
keywords: Amyloid-β toxicity; mitochondrial dysfunction; neuroprotection; selective estrogen receptor modulator