Cognitive Decline in Alzheimer's Disease Is Associated with Selective Changes in Calcineurin/NFAT Signaling

被引:254
作者
Abdul, Hafiz Mohmmad
Sama, Michelle A. [2 ]
Furman, Jennifer L. [2 ]
Mathis, Diana M. [3 ]
Beckett, Tina L.
Weidner, Adam M. [4 ]
Patel, Ela S.
Baig, Irfan
Murphy, M. Paul [4 ]
LeVine, Harry, III [4 ]
Kraner, Susan D. [2 ]
Norris, Christopher M. [1 ,2 ]
机构
[1] Univ Kentucky, Coll Med, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
[2] Univ Kentucky, Dept Mol & Biomed Pharmacol, Lexington, KY 40536 USA
[3] Univ Kentucky, Grad Ctr Gerontol, Lexington, KY 40536 USA
[4] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA
基金
美国国家卫生研究院;
关键词
ACTIVATED T-CELLS; AMYLOID-BETA; A-BETA; CALCIUM-CHANNELS; GLUTAMATE UPTAKE; GENE-EXPRESSION; CYCLOSPORINE-A; NUCLEAR FACTOR; NF-AT; ASTROCYTES;
D O I
10.1523/JNEUROSCI.1064-09.2009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 Ca2+ 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-A alpha 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 (A beta((1-42))) levels in postmortem hippocampus, and oligomeric A beta, in particular, robustly stimulated NFAT activation in primary rat astrocyte cultures. Oligomeric A beta 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 A beta-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 A beta-mediated neurodegeneration.
引用
收藏
页码:12957 / 12969
页数:13
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