Inhibition of the NFAT Pathway Alleviates Amyloid Beta Neurotoxicity in a Mouse Model of Alzheimer's Disease

Massachusetts General Hospital, Department of Neurology/Alzheimer's Disease Research Laboratory, Charlestown, Massachusetts 02129, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2012; 32(9):3176-92. DOI: 10.1523/JNEUROSCI.6439-11.2012
Source: PubMed


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.

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    • "See review Torres-Aleman, 2008; Perl, 2010 ↑Tau-P and NFT's Tran et al., 2011; Johnson et al., 2012b See review Torres-Aleman, 2008; Perl, 2010 Neuronal cell loss Baldwin et al., 1997; Wakade et al., 2010 See review Torres-Aleman, 2008; Perl, 2010 Synapse loss Wakade et al., 2010; Gao et al., 2011 Reddy and Beal, 2008; see review Arendt, 2009 Dendritic spine loss and remodeling Gao et al., 2011; Campbell et al., 2012a Knobloch and Mansuy, 2008; Hudry et al., 2012 Frontiers in "
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