Neuroregenerative mechanisms of allopregnanolone in Alzheimer's disease

Ronald W. Irwin, Jun Ming Wang, Shuhua Chen, Roberta Diaz Brinton

Research output: Contribution to journalReview articlepeer-review

20 Scopus citations

Abstract

The proliferative pool and regenerative potential of neural stem cells diminishes with age, a phenomenon that may be exacerbated in prodromal and mild Alzheimer's disease (AD) brains. In parallel, the neuroactive progesterone metabolite, allopregnanolone (APα), along with a host of other factors, is decreased in the AD brain. Results of preclinical analyses demonstrate that APα is a potent inducer of neural progenitor proliferation of both rodent and human derived neural progenitor cells in vitro. In vivo,APα significantly increased neurogenesis within the subgranular zone of the dentate gyrus and subventricular zone of the 3×TgAD mouse model. Functionally, APα reversed the learning and memory deficits of 3×TgAD mice prior to and following the onset of AD pathology and was comparably efficacious in aged normal mice. In addition to inducing regenerative responses in mouse models of AD, APα significantly reduced beta-amyloid burden, beta-amyloid binding alcohol dehydrogenase load, and microglial activation. In parallel, APα increased markers of white matter generation and cholesterol homeostasis. Analyses to determine the optimal treatment regimen in the 3×TgAD mouse brain indicated that a treatment regimen of APα once per week was optimal for both inducing neurogenesis and reducing AD pathology. Pharma-cokinetic analyses indicated that APα is rapidly increased in both plasma and brain following a single dose. APα is most efficacious when administered once per week which will contribute to its margin of safety. Further, analyses in both animals and humans have provided parameters for safe APα dosage exposure in humans. From a translational perspective, APα is a small molecular weight, blood brain barrier penetrant molecule with substantial preclinical efficacy data as a potential Alzheimer's therapeutic with existing safety data in animals and humans.To our knowledge, APα is the only small molecule that both promotes neural progenitor regeneration in brain and simultaneously reduces AD pathology burden.

Original languageEnglish (US)
Article numberArticle 117
JournalFrontiers in Endocrinology
Volume3
Issue numberJAN
DOIs
StatePublished - 2012
Externally publishedYes

Keywords

  • Allopregnanolone
  • Alzheimer's disease
  • Cholesterol homeostasis
  • Myelin
  • Neurogenesis
  • Regeneration
  • Treatment regimen
  • β-Amyloid

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

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