Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling.
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.
Abdul
Hafiz Mohmmad
HM
The Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536, USA.
Sama
Michelle A
MA
Furman
Jennifer L
JL
Mathis
Diana M
DM
Beckett
Tina L
TL
Weidner
Adam M
AM
Patel
Ela S
ES
Baig
Irfan
I
Murphy
M Paul
MP
LeVine
Harry
H
Kraner
Susan D
SD
Norris
Christopher M
CM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D050778:NFATC Transcription Factors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D019703:Calcineurin