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Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice


Year of Publication:
Contact PI Name:
Christian J. Pike
Contact PI Affiliation:
Davis School of Gerontology University of Southern California, Los Angeles, California, USA
Jenna C. Carroll, Emily R. Rosario, Lilly Chang, Frank Z. Stanczyk, Salvatore Oddo, Frank M. LaFerla
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
National Institute of Neurological Disorders and Stroke (NINDS)
Study Goal and Principal Findings:

This study investigated hormones progesterone and estrogen on Alzheimer neuropathology in female 3xTg-AD mice. Abundant evidence suggests that the depletion of the sex steroid hormones estrogen and progesterone  at menopause is a significant risk factor for the development of AD in women. Furthermore, prospective and case-control studies have demonstrated that hormone therapy (HT) can reduce the risk of AD in women. Given this background, findings from the Women’s Health Initiative Memory Study (WHIMS) demonstrating a higher incidence of dementia in subjects receiving estrogen based HT in the absence and presence of progestin were unexpected. In this study using gonadally intact female 3xTg-AD mice, AD-like neuropathology was apparent by 3 months of age and progressively increased through age 12 months, a time course that was paralleled by behavioral impairment. Ovariectomy-induced depletion of sex steroid hormones in adult female 3xTg-AD mice significantly increased Aβ  accumulation and worsened memory performance. Treatment of ovariectomized 3xTg-AD mice with estrogen, but not progesterone, prevented these effects. When estrogen and progesterone were administered in combination, progesterone blocked the beneficial effect of estrogen on Aβ accumulation but not on behavioral performance. Interestingly, progesterone significantly reduced tau hyperphosphorylation when administered both alone and in combination with estrogen. These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Hormone
Therapeutic Agent:
Therapeutic Target:
Progesterone Receptor
Therapy Type:
Biologic - Hormone
Therapeutic Agent:
Therapeutic Target:
Estrogen Receptor

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:

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
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


Outcome Measured
Outcome Parameters
Spontaneous Alternation
beta Amyloid Load
Brain-beta Amyloid Deposits
Amyloid Precursor Protein (APP)