Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease.

TitleAllopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2011
AuthorsChen S, Wang JMing, Irwin RW, Yao J, Liu L, Brinton RDiaz
JournalPLoS One
Volume6
Issue8
Paginatione24293
Date Published2011
ISSN1932-6203
Keywords2',3'-Cyclic-Nucleotide Phosphodiesterases, Alzheimer Disease, Amyloid, Amyloid beta-Peptides, Animals, Flow Cytometry, Humans, Hydroxymethylglutaryl CoA Reductases, Immunoblotting, Male, Mice, Microglia, Pregnanolone
Abstract

Previously, we demonstrated that allopregnanolone (APα) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APα promoted neurogenesis in the hippocampal subgranular zone (SGZ) and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD). In the current study, we determined the efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model. Comparative analyses between three different APα treatment regimens indicated that APα administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of APα to impact Aβ burden. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα significantly reduced Aβ generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Aβ-binding-alcohol-dehydrogenase. In addition, APα significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with APα increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R), three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of APα to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease.

DOI10.1371/journal.pone.0024293
Alternate JournalPLoS ONE
PubMed ID21918687
PubMed Central IDPMC3168882
Grant ListU01 AG031115 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D