RGD Reference Report - Allopregnanolone promotes regeneration and reduces beta-amyloid burden in a preclinical model of Alzheimer's disease. - Rat Genome Database

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

Authors: Chen, S  Wang, JM  Irwin, RW  Yao, J  Liu, L  Brinton, RD 
Citation: Chen S, etal., PLoS One. 2011;6(8):e24293. Epub 2011 Aug 30.
RGD ID: 6483333
Pubmed: PMID:21918687   (View Abstract at PubMed)
PMCID: PMC3168882   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0024293   (Journal Full-text)

Previously, we demonstrated that allopregnanolone (APalpha) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APalpha 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 APalpha 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 APalpha treatment regimens indicated that APalpha 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 APalpha to impact Abeta burden. Treatment was initiated either prior to or post intraneuronal Abeta accumulation. Results indicated that APalpha administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Abeta pathology with greatest efficacy in the pre-pathology treatment group. APalpha significantly reduced Abeta generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Abeta-binding-alcohol-dehydrogenase. In addition, APalpha 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 APalpha 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 APalpha to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease  ISOCnp (Mus musculus)6483333; 6483333 RGD 
Alzheimer's disease  IDA 6483333 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cnp  (2',3'-cyclic nucleotide 3' phosphodiesterase)

Genes (Mus musculus)
Cnp  (2',3'-cyclic nucleotide 3' phosphodiesterase)

Genes (Homo sapiens)
CNP  (2',3'-cyclic nucleotide 3' phosphodiesterase)


Additional Information