| First Author | Hudry E | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 9 | Pages | 3176-92 |
| PubMed ID | 22378890 | Mgi Jnum | J:182683 |
| Mgi Id | MGI:5316328 | Doi | 10.1523/JNEUROSCI.6439-11.2012 |
| Citation | Hudry E, et al. (2012) Inhibition of the NFAT pathway alleviates amyloid beta neurotoxicity in a mouse model of Alzheimer's disease. J Neurosci 32(9):3176-92 |
| abstractText | Amyloid beta (Abeta) 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 Abeta leads to pathological morphological changes in neurons, and overexpression of constitutively active calcineurin is sufficient to generate a similar phenotype, even without Abeta. 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 Abeta 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 Abeta-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 Abeta synaptotoxicity, and may provide a new specific set of pathways for neuroprotective strategies. |
