title: Treatment of beta amyloid 1-42 (Aβ(1-42))-induced basal forebrain cholinergic damage by a non-classical estrogen signaling activator in vivo.
abstract: In Alzheimer's disease (AD), there is a loss in cholinergic innervation targets of basal forebrain which has been implicated in substantial cognitive decline. Amyloid beta peptide (Aβ(1-42)) accumulates in AD that is highly toxic for basal forebrain cholinergic (BFC) neurons. Although the gonadal steroid estradiol is neuroprotective, the administration is associated with risk of off-target effects. Previous findings suggested that non-classical estradiol action on intracellular signaling pathways has ameliorative potential without estrogenic side effects. After Aβ(1-42) injection into mouse basal forebrain, a single dose of 4-estren-3α, 17β-diol (estren), the non-classical estradiol pathway activator, restored loss of cholinergic cortical projections and also attenuated the Aβ(1-42)-induced learning deficits. Estren rapidly and directly phosphorylates c-AMP-response-element-binding-protein and extracellular-signal-regulated-kinase-1/2 in BFC neurons and restores the cholinergic fibers via estrogen receptor-α. These findings indicated that selective activation of non-classical intracellular estrogen signaling has a potential to treat the damage of cholinergic neurons in AD.
authors.affiliation: Centre for Neuroendocrinology and Department of Physiology, Otago Medical School, University of Otago, Dunedin, New Zealand.|Centre for Brain Research and Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kwakowsky
authors.affiliation: Centre for Neuroendocrinology and Department of Physiology, Otago Medical School, University of Otago, Dunedin, New Zealand.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Potapov
authors.affiliation: Centre for Neuroendocrinology and Department of Physiology, Otago Medical School, University of Otago, Dunedin, New Zealand.
authors.forename: SooHyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Otago Medical School, University of Otago, Dunedin, New Zealand.
authors.forename: Katie
authors.initials: K
authors.lastname: Peppercorn
authors.affiliation: Department of Biochemistry, Otago Medical School, University of Otago, Dunedin, New Zealand.
authors.forename: Warren P
authors.initials: WP
authors.lastname: Tate
authors.affiliation: Centre for Neuroendocrinology and Department of Physiology, Otago Medical School, University of Otago, Dunedin, New Zealand.|MTA-NAP-B-Molecular Neuroendocrinology Research Group, Centre for Neuroscience, Szentágothai Research Centre, Institute of Physiology, Medical School, University of Pécs, Pécs, Hungary.
authors.forename: István M
authors.initials: IM
authors.lastname: Ábrahám
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D066187:Basal Forebrain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D007858:Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D013003:Somatosensory Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D047628:Estrogen Receptor alpha; D004967:Estrogens; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)