Abstract
Several studies have linked stress with Alzheimer's disease (AD) vulnerability; however, the mechanism remains to be fully elucidated. In the current paper, we investigated the role of glucocortitcoids on the AD-like phenotype. We administered the glucocorticoid dexamethasone to Tg2576 mice for 4 weeks and then investigated its effect on memory, amyloid-β and tau levels, and metabolism. At the end of the treatment period, we observed that mice receiving dexamethasone had a significant impairment in the fear conditioning paradigm compared with controls. Dexamethasone-treated animals showed a significant increase in the amount of brain soluble Aβ40 levels, but no alteration in the steady state levels of its precursor protein, AβPP, or in the major protease enzymes involved in its metabolism (i.e., ADAM-10, BACE-1, or γ-secretase complex). While total tau protein levels were unaltered between the two groups, we found that dexamethasone significantly reduced tau phosphorylation at specific sites that were mediated by decreases in glycogen synthase kinase-3β protein level activity. Finally, we observed a direct correlation between memory impairments and tau phosphorylation levels. Our study highlights the significant role that glucocorticoids play in exacerbating AD-like cognitive impairments via alteration of tau protein phosphorylation state.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ADAM Proteins / metabolism
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ADAM10 Protein
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Alzheimer Disease / complications*
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Alzheimer Disease / metabolism*
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Protein Precursor / genetics
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Animals
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Aspartic Acid Endopeptidases / metabolism
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Conditioning, Psychological / drug effects
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Conditioning, Psychological / physiology
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Dexamethasone / adverse effects*
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Disease Models, Animal
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Enzyme-Linked Immunosorbent Assay
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Fear / drug effects
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Female
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Glucocorticoids / adverse effects*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Immunoprecipitation
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Membrane Proteins / metabolism
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Memory Disorders / chemically induced*
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Memory Disorders / metabolism
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Memory Disorders / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics
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Nerve Tissue Proteins / metabolism
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Phosphorylation / drug effects
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Phosphorylation / genetics
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tau Proteins / metabolism*
Substances
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Amyloid beta-Protein Precursor
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Glucocorticoids
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Membrane Proteins
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Nerve Tissue Proteins
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tau Proteins
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Dexamethasone
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Glycogen Synthase Kinase 3
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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ADAM Proteins
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ADAM10 Protein
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ADAM10 protein, human