title: Nonsteroidal selective androgen receptor modulators and selective estrogen receptor β agonists moderate cognitive deficits and amyloid-β levels in a mouse model of Alzheimer's disease.
abstract: Decreases of the sex steroids, testosterone and estrogen, are associated with increased risk of Alzheimer's disease. Testosterone and estrogen supplementation improves cognitive deficits in animal models of Alzheimer's disease. Sex hormones play a role in the regulation of amyloid-β via induction of the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme. To mimic the effect of dihydrotestosterone (DHT), we administered a selective androgen receptor agonist, ACP-105, alone and in combination with the selective estrogen receptor β (ERβ) agonist AC-186 to male gonadectomized triple transgenic mice. We assessed long-term spatial memory in the Morris water maze, spontaneous locomotion, and anxiety-like behavior in the open field and in the elevated plus maze. We found that ACP-105 given alone decreases anxiety-like behavior. Furthermore, when ACP-105 is administered in combination with AC-186, they increase the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme and decrease amyloid-β levels in the brain as well as improve cognition. Interestingly, the androgen receptor level in the brain was increased by chronic treatment with the same combination treatment, ACP-105 and AC-186, not seen with DHT or ACP-105 alone. Based on these results, the beneficial effect of the selective ERβ agonist as a potential therapeutic for Alzheimer's disease warrants further investigation.
authors.affiliation: Neuronal Survival Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University , Lund S-22184, Sweden.
authors.forename: Sonia
authors.initials: S
authors.lastname: George
authors.forename: Géraldine H
authors.initials: GH
authors.lastname: Petit
authors.forename: Gunnar K
authors.initials: GK
authors.lastname: Gouras
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003510:Cyclohexanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D047629:Estrogen Receptor beta / Q000819:agonists*; D006801:Humans; D007150:Immunohistochemistry; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology
chemical_list: C587712:AC-186; D000728:Androgens; D003510:Cyclohexanes; D047629:Estrogen Receptor beta; D010636:Phenols
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