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The Journal of Neuroscience, October 14, 2009, 29(41):12957-12969; doi:10.1523/JNEUROSCI.1064-09.2009

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

Hafiz Mohmmad Abdul,¹ Michelle A. Sama,² Jennifer L. Furman,² Diana M. Mathis,³ Tina L. Beckett,¹ Adam M. Weidner,⁴ Ela S. Patel,¹ Irfan Baig,¹ M. Paul Murphy,^1,4 Harry LeVine 3rd,^1,4 Susan D. Kraner,² and Christopher M. Norris^1,2

¹The Sanders-Brown Center on Aging, ²Department of Molecular and Biomedical Pharmacology, ³Graduate Center for Gerontology, and ⁴Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536

Correspondence should be addressed to Dr. Christopher M. Norris, 131 Sanders-Brown Building, 800 South Limestone Street, University of Kentucky College of Medicine, Lexington, KY 40536. Email: cnorr2{at}email.uky.edu

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 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-β (Aβ_(1-42)) levels in postmortem hippocampus, and oligomeric Aβ, in particular, robustly stimulated NFAT activation in primary rat astrocyte cultures. Oligomeric Aβ 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 Aβ-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 Aβ-mediated neurodegeneration.

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Received March 4, 2009; revised Aug. 20, 2009; accepted Sept. 2, 2009.

Correspondence should be addressed to Dr. Christopher M. Norris, 131 Sanders-Brown Building, 800 South Limestone Street, University of Kentucky College of Medicine, Lexington, KY 40536. Email: cnorr2{at}email.uky.edu

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