RT Journal Article
SR Electronic
T1 Inhibition of the NFAT Pathway Alleviates Amyloid Beta Neurotoxicity in a Mouse Model of Alzheimer's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3176
OP 3192
DO 10.1523/JNEUROSCI.6439-11.2012
VO 32
IS 9
A1 Eloise Hudry
A1 Hai-Yan Wu
A1 Michal Arbel-Ornath
A1 Tadafumi Hashimoto
A1 Roland Matsouaka
A1 Zhanyun Fan
A1 Tara L. Spires-Jones
A1 Rebecca A. Betensky
A1 Brian J. Bacskai
A1 Bradley T. Hyman
YR 2012
UL http://www.jneurosci.org/content/32/9/3176.abstract
AB Amyloid β (Aβ) peptides, the main pathological species associated with Alzheimer's disease (AD), disturb intracellular calcium homeostasis, which in turn activates the calcium-dependent phosphatase calcineurin (CaN). CaN activation induced by Aβ leads to pathological morphological changes in neurons, and overexpression of constitutively active calcineurin is sufficient to generate a similar phenotype, even without Aβ. Here, we tested the hypothesis that calcineurin mediates neurodegenerative effects via activation of the nuclear transcription factor of activated T-cells (NFAT). We found that both spine loss and dendritic branching simplification induced by Aβ exposure were mimicked by constitutively active NFAT, and abolished when NFAT activation was blocked using the genetically encoded inhibitor VIVIT. When VIVIT was specifically addressed to the nucleus, identical beneficial effects were observed, thus enforcing the role of NFAT transcriptional activity in Aβ-related neurotoxicity. In vivo, when VIVIT or its nuclear counterpart were overexpressed in a transgenic model of Alzheimer's disease via a gene therapy approach, the spine loss and neuritic abnormalities observed in the vicinity of amyloid plaques were blocked. Overall, these results suggest that NFAT/calcineurin transcriptional cascades contribute to Aβ synaptotoxicity, and may provide a new specific set of pathways for neuroprotective strategies.