| Title | Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling. | | Author(s) | Abdul HM, Sama MA, Furman JL, Mathis DM, Beckett TL, Weidner AM, Patel ES, Baig I, Murphy MP, LeVine H, Kraner SD, Norris CM | | Institution | The Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536, USA. | | Source | J Neurosci 2009 Oct 14; 29(41):12957-69. | | MeSH | Aged
Aged, 80 and over
Alzheimer Disease
Amyloid beta-Protein
Analysis of Variance
Animals
Astrocytes
Brain
Calcineurin
Cells, Cultured
Cognition Disorders
Embryo, Mammalian
Female
Gene Expression Regulation
Glial Fibrillary Acidic Protein
Glutamic Acid
Green Fluorescent Proteins
Hippocampus
Humans
Male
NFATC Transcription Factors
Peptide Fragments
Protein Transport
Rats
Signal Transduction
Transfection
| | Abstract | Upon activation by calcineurin, the nuclear factor of activated T-cells (NFAT) translocates to the nucleus and guides the transcription of numerous molecules involved in inflammation and Ca(2+) dysregulation, both of which are prominent features of Alzheimer's disease (AD). However, NFAT signaling in AD remains relatively uninvestigated. Using isolated cytosolic and nuclear fractions prepared from rapid-autopsy postmortem human brain tissue, we show that NFATs 1 and 3 shifted to nuclear compartments in the hippocampus at different stages of neuropathology and cognitive decline, whereas NFAT2 remained unchanged. NFAT1 exhibited greater association with isolated nuclear fractions in subjects with mild cognitive impairment (MCI), whereas NFAT3 showed a strong nuclear bias in subjects with severe dementia and AD. Similar to NFAT1, calcineurin-Aalpha also exhibited a nuclear bias in the early stages of cognitive decline. But, unlike NFAT1 and similar to NFAT3, the nuclear bias for calcineurin became more pronounced as cognition worsened. Changes in calcineurin/NFAT3 were directly correlated to soluble amyloid-beta (Abeta((1-42))) levels in postmortem hippocampus, and oligomeric Abeta, in particular, robustly stimulated NFAT activation in primary rat astrocyte cultures. Oligomeric Abeta also caused a significant reduction in excitatory amino acid transporter 2 (EAAT2) protein levels in astrocyte cultures, which was blocked by NFAT inhibition. Moreover, inhibition of astrocytic NFAT activity in mixed cultures ameliorated Abeta-dependent elevations in glutamate and neuronal death. The results suggest that NFAT signaling is selectively altered in AD and may play an important role in driving Abeta-mediated neurodegeneration. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
| | PubMed ID | 19828810 |
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