Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Jun Ming Wang, Chanpreet Singh, Lifei Liu, Ronald W. Irwin, Shuhua Chen, Eun Ji Chung, Richard F. Thompson, Roberta Diaz Brinton

Research output: Contribution to journalArticlepeer-review

219 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6498-6503
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number14
DOIs
StatePublished - Apr 6 2010
Externally publishedYes

Keywords

  • Adult neurogenesis
  • Alzheimer's therapeutics
  • Subgranular zone
  • Trace eyeblink conditioning
  • Translational neuroscience

ASJC Scopus subject areas

  • General

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