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


BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2011
Contact PI Name:
Roberta Diaz Brinton
Contact PI Affiliation:
Department of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America
Co-Authors:
S. Chen, J.M. Wang, R.W. Irwin, J. Yao, L. Liu
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Drug Discovery Foundation (ADDF)
Kenneth T. and Eileen L. Norris Foundation
Study Goal and Principal Findings:

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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Hormone
Therapeutic Agent:
Allopregnanolone (APα)
Therapeutic Target:
GABA-A Receptor

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1xTau
Strain/Genetic Background:
C57BL6/129S

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Experiment Notes

Only offspring from breeders that exhibited stable AD pathology were included in the study

Outcomes

Outcome Measured
Outcome Parameters
Histopathology
beta Amyloid Deposits
Activated Microglia
Tau Pathology
Biochemical
Brain-beta Amyloid Oligomers
phospho-Tau
Amyloid Binding Alcohol Dehydrogenase (ABAD)
Endoplasmic Reticulum-Associated Amyloid Beta-Peptide-Binding Protein (ERAB)
CD11b/c
3-hydroxy-3-methylglutaryl Coenzyme A Reductase (HMG-CoA-R)
Inducible Liver X Receptor (LXR)
Pregnane X Receptor (PXR)
2',3'-cyclic-nucleotide-3'-phosphodiesterase (CNP)
Brain-beta Amyloid Peptide-Total
Immunochemistry
Brain-beta Amyloid Oligomers
Neurogenesis
5-bromo-2’-deoxyuridine (BrdU)
5-chloro-2'-deoxyuridine (CldU)
Idoxuridine (IdU)
Cell Survival
Activated Microglia
CD11b/c
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
Endoplasmic Reticulum-Associated Amyloid Beta-Peptide-Binding Protein (ERAB)
Activated Oligodendrocytes
2',3'-cyclic-nucleotide-3'-phosphodiesterase (CNP)
Brain-beta Amyloid Peptides
phospho-Tau
Microscopy
Stereology
Cell Biology
Flow Cytometry
FACS Analysis

Source URL: http://alzped.nia.nih.gov/allopregnanolone-promotes