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...  Read more

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:
1. Norris CM et al. (2005) Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer's models. J Neurosci 25:4649-4658. Abstract

2. Dineley KT et al (2007) Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem 88:217-224. Abstract

3. Wu HY et al. (2010) Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 30:2636-2649. Abstract

4. Liu F. et al. Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem 280, 37755-37762. Abstract

5. Abdul HM et al. (2009) Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci 29, 12957-12969. Abstract

6. Mohmmad Abdul H, et al (2011) Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated in primary neuronal cultures by oligomeric Abeta. Aging Cell, 10:103-113. Abstract

7. Yoshiyama Y et al (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 53:337-51. Abstract

8. Cho HJ et al. RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer's disease animal model. FASEB J 23, 2639-2649. Abstract

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