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PMID: 16943563 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 26 ·No. 35 ·2006-08-30 ·Pages 9047-56

Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM

Abstract

Various environmental and genetic factors influence the onset and progression of Alzheimer's disease (AD). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which controls circulating levels of glucocorticoid hormones, occurs early in AD, resulting in increased cortisol levels. Disturbances of the HPA axis have been associated with memory impairments and may contribute to the cognitive decline that occurs in AD, although it is unknown whether such effects involve modulation of the amyloid beta-peptide (Abeta) and tau. Using in vitro and in vivo experiments, we report that stress-level glucocorticoid administration increases Abeta formation by increasing steady-state levels of amyloid precursor protein (APP) and beta-APP cleaving enzyme. Additionally, glucocorticoids augment tau accumulation, indicating that this hormone also accelerates the development of neurofibrillary tangles. These findings suggest that high levels of glucocorticoids, found in AD, are not merely a consequence of the disease process but rather play a central role in the development and progression of AD.

MeSH Terms
Alzheimer Disease/genetics,metabolism,pathology Amyloid Precursor Protein Secretases Amyloid beta-Peptides/biosynthesis,chemistry,metabolism Amyloid beta-Protein Precursor/genetics,metabolism Animals Aspartic Acid Endopeptidases Brain/metabolism,pathology Cell Line Corticosterone/blood Dendrites/metabolism Dexamethasone/pharmacology Disease Models, Animal Dose-Response Relationship, Drug Endopeptidases/metabolism Glucocorticoids/administration & dosage,metabolism,pharmacology Male Mice Mice, Transgenic Neurons/metabolism Solubility Stress, Physiological/metabolism Time Factors Transgenes tau Proteins/metabolism
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor Glucocorticoids tau Proteins Dexamethasone Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases Bace1 protein, mouse Corticosterone
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Green Kim N
Department of Neurobiology and Behavior, and Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, California 92697-4545, USA.
Billings Lauren M
Roozendaal Benno
McGaugh James L
LaFerla Frank M
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.2797-06.2006
Published
2006-08-30
Pages
9047-56
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6675335
Subset
IM
Grants
NIMH NIH HHS · R01 MH012526 · United States
NIMH NIH HHS · R56 MH012526 · United States
NIA NIH HHS · AG0212982 · United States
NIMH NIH HHS · MH-12526 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.2797-06.2006 PMC Full Text View journal details
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