PMID- 19828810
OWN - NLM
STAT- MEDLINE
DCOM- 20091030
LR  - 20220408
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 29
IP  - 41
DP  - 2009 Oct 14
TI  - Cognitive decline in Alzheimer's disease is associated with selective changes in 
      calcineurin/NFAT signaling.
PG  - 12957-69
LID - 10.1523/JNEUROSCI.1064-09.2009 [doi]
AB  - 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.
FAU - Abdul, Hafiz Mohmmad
AU  - Abdul HM
AD  - The Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 
      40536, USA.
FAU - Sama, Michelle A
AU  - Sama MA
FAU - Furman, Jennifer L
AU  - Furman JL
FAU - Mathis, Diana M
AU  - Mathis DM
FAU - Beckett, Tina L
AU  - Beckett TL
FAU - Weidner, Adam M
AU  - Weidner AM
FAU - Patel, Ela S
AU  - Patel ES
FAU - Baig, Irfan
AU  - Baig I
FAU - Murphy, M Paul
AU  - Murphy MP
FAU - LeVine, Harry 3rd
AU  - LeVine H 3rd
FAU - Kraner, Susan D
AU  - Kraner SD
FAU - Norris, Christopher M
AU  - Norris CM
LA  - eng
GR  - P01 AG010836-14/AG/NIA NIH HHS/United States
GR  - P50 AG005144-19/AG/NIA NIH HHS/United States
GR  - RF1 AG027297/AG/NIA NIH HHS/United States
GR  - P01 AG010836-13/AG/NIA NIH HHS/United States
GR  - P01 AG010836/AG/NIA NIH HHS/United States
GR  - K01 AG024190-04/AG/NIA NIH HHS/United States
GR  - R01 AG027297-03/AG/NIA NIH HHS/United States
GR  - AG024190/AG/NIA NIH HHS/United States
GR  - AG010836/AG/NIA NIH HHS/United States
GR  - P30 AG028383/AG/NIA NIH HHS/United States
GR  - R01 AG027297/AG/NIA NIH HHS/United States
GR  - K01 AG024190-05/AG/NIA NIH HHS/United States
GR  - AG02797/AG/NIA NIH HHS/United States
GR  - AG028383/AG/NIA NIH HHS/United States
GR  - K01 AG024190-02/AG/NIA NIH HHS/United States
GR  - P50 AG005144-18/AG/NIA NIH HHS/United States
GR  - R01 AG027297-02/AG/NIA NIH HHS/United States
GR  - P50 AG005144-17/AG/NIA NIH HHS/United States
GR  - P01 AG010836-12/AG/NIA NIH HHS/United States
GR  - K01 AG024190-03/AG/NIA NIH HHS/United States
GR  - P50 AG005144-20/AG/NIA NIH HHS/United States
GR  - K01 AG024190/AG/NIA NIH HHS/United States
GR  - P50 AG005144/AG/NIA NIH HHS/United States
GR  - R01 AG027297-01A1/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (Peptide Fragments)
RN  - 0 (amyloid beta-protein (1-42))
RN  - 0 (enhanced green fluorescent protein)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - EC 3.1.3.16 (Calcineurin)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Alzheimer Disease/complications/metabolism
MH  - Amyloid beta-Peptides/pharmacology
MH  - Analysis of Variance
MH  - Animals
MH  - Astrocytes/drug effects
MH  - Brain/metabolism/pathology
MH  - Calcineurin/*metabolism
MH  - Cells, Cultured
MH  - Cognition Disorders/*etiology/*metabolism/pathology
MH  - Embryo, Mammalian
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Glutamic Acid/metabolism
MH  - Green Fluorescent Proteins/genetics
MH  - Hippocampus/cytology
MH  - Humans
MH  - Male
MH  - NFATC Transcription Factors/*metabolism
MH  - Peptide Fragments/pharmacology
MH  - Protein Transport/genetics
MH  - Rats
MH  - Signal Transduction/*physiology
MH  - Transfection
PMC - PMC2782445
MID - NIHMS158049
EDAT- 2009/10/16 06:00
MHDA- 2009/10/31 06:00
PMCR- 2010/04/14
CRDT- 2009/10/16 06:00
PHST- 2009/10/16 06:00 [entrez]
PHST- 2009/10/16 06:00 [pubmed]
PHST- 2009/10/31 06:00 [medline]
PHST- 2010/04/14 00:00 [pmc-release]
AID - 29/41/12957 [pii]
AID - 3534819 [pii]
AID - 10.1523/JNEUROSCI.1064-09.2009 [doi]
PST - ppublish
SO  - J Neurosci. 2009 Oct 14;29(41):12957-69. doi: 10.1523/JNEUROSCI.1064-09.2009.