Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease.
Our previous analyses showed that allopregnanolone (APalpha) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APalpha to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between APalpha-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells. Learning and memory function was assessed using the hippocampal-dependent trace eye-blink conditioning paradigm. At 3 months, basal level of BrdU+ cells in the SGZ of 3xTgAD mice was significantly lower relative to non-Tg mice, despite the lack of evident AD pathology. APalpha significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude. As with the deficit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. APalpha reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APalpha-induced survival of neural progenitors was significantly correlated with APalpha-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Abeta, may contribute to the cognitive phenotype of AD, and that APalpha could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern [corrected] California, Los Angeles, CA 90089, USA.
Jun Ming
JM
Wang
Chanpreet
C
Singh
Lifei
L
Liu
Ronald W
RW
Irwin
Shuhua
S
Chen
Eun Ji
EJ
Chung
Richard F
RF
Thompson
Roberta Diaz
RD
Brinton
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology*; D011280:Pregnanolone / Q000627:therapeutic use*; D013234:Stem Cells / Q000166:cytology
D016229:Amyloid beta-Peptides; D011280:Pregnanolone