title: Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice.
abstract: We previously demonstrated that allopregnanolone (APα) increased proliferation of neural progenitor cells and reversed neurogenic and cognitive deficits prior to Alzheimer's disease (AD) pathology (Wang, J.M., Johnston, P.B., Ball, B.G., Brinton, R.D., 2005. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J. Neurosci. 25, 4706-4718; Wang, J.M., Singh, C., Liu, L., Irwin, R.W., Chen, S., Chung, E.J., Thompson, R.F., Brinton, R.D., 2010. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 107, 6498-6503). Herein, we determined efficacy of APα to restore neural progenitor cell survival and associative learning and memory subsequent to AD pathology in male 3xTgAD mice and their nontransgenic (nonTg) counterparts. APα significantly increased survival of bromodeoxyuridine positive (BrdU+) cells and hippocampal-dependent associative learning and memory in 3xTgAD mice in the presence of intraneuronal amyloid beta (Aβ) whereas APα was ineffective subsequent to development of extraneuronal Aβ plaques. Restoration of hippocampal-dependent associative learning was maximal by the first day and sustained throughout behavioral training. Learning and memory function in APα-treated 3xTgAD mice was 100% greater than vehicle-treated and comparable to maximal normal nonTg performance. In aged 15-month-old nonTg mice, APα significantly increased survival of bromodeoxyuridine-positive cells and hippocampal-dependent associative learning and memory. Results provide preclinical evidence that APα promoted survival of newly generated cells and restored cognitive performance in the preplaque phase of AD pathology and in late-stage normal aging.
authors.affiliation: Neuroscience Program, University of Southern California, Los Angeles, CA 90089-9121, USA.
authors.forename: Chanpreet
authors.initials: C
authors.lastname: Singh
authors.forename: Lifei
authors.initials: L
authors.lastname: Liu
authors.forename: Jun Ming
authors.initials: JM
authors.lastname: Wang
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Irwin
authors.forename: Jia
authors.initials: J
authors.lastname: Yao
authors.forename: Shuhua
authors.initials: S
authors.lastname: Chen
authors.forename: Sherry
authors.initials: S
authors.lastname: Henry
authors.forename: Richard F
authors.initials: RF
authors.lastname: Thompson
authors.forename: Roberta Diaz
authors.initials: RD
authors.lastname: Brinton
mesh_terms: D000375:Aging / Q000187:drug effects*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002470:Cell Survival; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D007858:Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D011280:Pregnanolone / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D011280:Pregnanolone