TY - JOUR
T1 - Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease
AU - Wang, Jun Ming
AU - Singh, Chanpreet
AU - Liu, Lifei
AU - Irwin, Ronald W.
AU - Chen, Shuhua
AU - Chung, Eun Ji
AU - Thompson, Richard F.
AU - Brinton, Roberta Diaz
PY - 2010/4/6
Y1 - 2010/4/6
N2 - Our previous analyses showed that allopregnanolone (APα) significantly increased proliferationof rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APα 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 APα-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. APα significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgADmice andrestoredSGZ proliferation to normalmagnitude. As with the de.cit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. APaα reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APα-induced survival of neural progenitors was significantly correlated with APα-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Aaβ, may contribute to the cognitive phenotype of AD, and that APα could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.
AB - Our previous analyses showed that allopregnanolone (APα) significantly increased proliferationof rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APα 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 APα-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. APα significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgADmice andrestoredSGZ proliferation to normalmagnitude. As with the de.cit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. APaα reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APα-induced survival of neural progenitors was significantly correlated with APα-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Aaβ, may contribute to the cognitive phenotype of AD, and that APα could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.
KW - Adult neurogenesis
KW - Alzheimer's therapeutics
KW - Subgranular zone
KW - Trace eyeblink conditioning
KW - Translational neuroscience
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UR - http://www.scopus.com/inward/citedby.url?scp=77950868172&partnerID=8YFLogxK
U2 - 10.1073/pnas.1001422107
DO - 10.1073/pnas.1001422107
M3 - Article
C2 - 20231471
AN - SCOPUS:77950868172
SN - 0027-8424
VL - 107
SP - 6498
EP - 6503
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -