. Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature. 2011 Feb 17;470(7334):404-8. PubMed.

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  1. Calcineurin is increasingly recognized for its important roles in brain aging and age-related neurodegenerative diseases. Several recent studies have shown that neural calcineurin signaling is augmented in mouse models of Alzheimer’s disease (AD) (e.g., 1-3) and in human subjects with AD (2,4,5) or mild cognitive impairment (5,6), contributing to synapse dysfunction (e.g., 3), neuroinflammation (e.g., 1,7), amyloidosis (e.g., 8), impaired memory (e.g., 2), and neurodegeneration in general. The new article by Mair et al. provides important confirmation of earlier studies that reported a negative impact of calcineurin activity on longevity in C. elegans. Moreover, Mair et al. provide compelling evidence that calcineurin regulates lifespan as part of a molecular pathway involving AMPK, CRTC-1, CREB, and possibly other signaling components related to ER stress. It will be critical to further characterize these molecular interactions and their functional outcomes in mammalian models of aging and AD, especially given the vast number of interspecies differences in cellular metabolism, gene regulation, and overall biological complexity. Nevertheless, Virginia Lee and John Trojanowski’s group recently showed that systemic delivery of the calcineurin inhibitor, FK-506, increases lifespan in a mouse model of tauopathy (7), indicating that calcineurin’s role in longevity may indeed be conserved between C. elegans and mammals.

    References:

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    . Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem. 2007 Sep;88(2):217-24. PubMed.

    . Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci. 2010 Feb 17;30(7):2636-49. PubMed.

    . Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem. 2005 Nov 11;280(45):37755-62. PubMed.

    . Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci. 2009 Oct 14;29(41):12957-69. PubMed.

    . Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated by oligomeric Abeta in primary cell culture. Aging Cell. 2011 Feb;10(1):103-13. PubMed.

    . Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51. PubMed.

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