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Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer's disease


Year of Publication:
Contact PI Name:
Frank M. LaFerla
Contact PI Affiliation:
Department of Neurobiology and Behavior University of California Irvine, California, USA
Kim N. Green, Lauren M. Billings, Benno Roozendaal, James L. McGaugh
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Association
National Institute on Aging (NIA)
National Institute of Mental Health (NIMH)
Study Goal and Principal Findings:

The present study sought to determine whether glucocorticoids modulate the hallmark neuropathological features of AD and, if so, the underlying mechanism. To this end the authors investigated the pathological consequences of stress-level glucocorticoid administration on Abeta formation and tau biology using both in vitro and in vivo approaches. Here the authors report the novel findings that levels of the beta-secretase enzyme [beta-APP cleaving enzyme (BACE)] and its substrate APP are selectively increased after glucocorticoid administration, resulting in increased production of Abeta peptides. Notably, administering glucocorticoids to the triple transgenic (3Tg-AD) mice, which develop both Abeta and tau pathologies in an age-dependent manner, exacerbated the formation of both lesions. The present findings highlight a mechanism by which stress affects AD neuropathology and suggest that stress management or pharmacological reduction of glucocorticoids warrant additional consideration in the regimen of AD therapies.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Hormone
Therapeutic Agent:
Therapeutic Target:
Glucocorticoid Receptors
Therapy Type:
Biologic - Hormone
Therapeutic Agent:
Therapeutic Target:
Mineralocorticoid Receptors
Therapeutic Notes:
Glucocorticoid Receptor has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
129/ C57BL/6

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
Activated Microglia
Tau Pathology
Brain-Detergent Insoluble beta Amyloid Peptide 40
Brain-Detergent Insoluble beta Amyloid Peptide 42
APP-CTF83 (CTF alpha)
APP-CTF99 (CTF beta)
Glucocorticoid Receptor
Brain-Detergent Soluble beta Amyloid Peptide 40
Brain-Detergent Soluble beta Amyloid Peptide 42
Activated Microglia