Calcineurin Links Ca<sup>2+</sup>Dysregulation with Brain Aging

Foster, Thomas C.; Sharrow, Keith M; Masse, James; Norris, Christopher M.; Kumar, Ashok

doi:10.1523/jneurosci.21-11-04066.2001

Cited by 199 publications

(165 citation statements)

References 64 publications

(91 reference statements)

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“…Although calcineurin activity declines during the postnatal period, it nonetheless remains important for normal hippocampal function in the adult (55), suggesting that its activity needs to be well titrated. In fact, both dysregulated calcineurin activity (56) and a marked decrease in STAT3 (57) have been observed in the aged brain. Therefore, the connections between calcineurin activity and neuronal survival signaling reported here are likely to contribute to novel approaches to treat neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Signal Transducer and Activator of Transcription 3 (STAT3) Degradation by Proteasome Controls a Developmental Switch in Neurotrophin Dependence

Murase

2013

Journal of Biological Chemistry

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Background: As neonatal hippocampal neurons mature, STAT3 levels increase via an unknown mechanism, which makes neurons neurotrophin-independent. Results: STAT3 protein levels are low in neonates because of calcineurin-dependent proteasomal degradation of STAT3. Conclusion: Calcineurin-dependent STAT3 degradation regulates the survival of neonatal neurons. Significance: Proteasomal degradation controls the developmental switch of neurotrophin dependence.

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Section: Discussionmentioning

confidence: 99%

Signal Transducer and Activator of Transcription 3 (STAT3) Degradation by Proteasome Controls a Developmental Switch in Neurotrophin Dependence

Murase

2013

Journal of Biological Chemistry

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“…5). However, considerable evidence indicates that Ca 2ϩ regulation is altered in hippocampal neurons during normal aging or in Tg models of AD (Landfield et al, 1989;Disterhoft et al, 1994;Foster and Norris, 1997;Thibault et al, 1998Thibault et al, , 2001Leissring et al, 2000;Mattson et al, 2000;Toescu et al, 2004), which may lead to increased calcineurin activity, with or without a change in expression (Foster et al, 2001). An age-related increase in neuronal calcineurin activity is consistent with studies showing "aging-like" memory deficits in forebrainspecific, calcineurin-overexpressing mice (Mayford and Kandel, 1999;Mansuy, 2003).…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

Norris

Kadish²,

Blalock³

et al. 2005

J. Neurosci.

202

210

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Astrocyte reactivity (i.e., activation) and associated neuroinflammation are increasingly thought to contribute to neurodegenerative disease. However, the mechanisms that trigger astrocyte activation are poorly understood. Here, we studied the Ca 2ϩ -dependent phosphatase calcineurin, which regulates inflammatory signaling pathways in immune cells, for a role in astrogliosis and brain neuroinflammation. Adenoviral transfer of activated calcineurin to primary rat hippocampal cultures resulted in pronounced thickening of astrocyte somata and processes compared with uninfected or virus control cultures, closely mimicking the activated hypertrophic phenotype. This effect was blocked by the calcineurin inhibitor cyclosporin A. Parallel microarray studies, validated by extensive statistical analyses, showed that calcineurin overexpression also induced genes and cellular pathways representing most major markers associated with astrocyte activation and recapitulated numerous changes in gene expression found previously in the hippocampus of normally aging rats or in Alzheimer's disease (AD). No genomic or morphologic evidence of apoptosis or damage to neurons was seen, indicating that the calcineurin effect was mediated by direct actions on astrocytes. Moreover, immunocytochemical studies of the hippocampus/neocortex in normal aging and AD model mice revealed intense calcineurin immunostaining that was highly selective for activated astrocytes. Together, these studies show that calcineurin overexpression is sufficient to trigger essentially the full genomic and phenotypic profiles associated with astrocyte activation and that hypertrophic astrocytes in aging and AD models exhibit dramatic upregulation of calcineurin. Thus, the data identify calcineurin upregulation in astrocytes as a novel candidate for an intracellular trigger of astrogliosis, particularly in aging and AD brain.

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“…Because constitutively expressed CREB is comparable across ages, mechanisms upstream of CREB activation may represent the primary deficit. While the bases for the decreased pCREB responses to training in aged rats are not clear, possible mechanisms include dysregulation of calcium fluxes (e.g., Disterhoft et al 1994;Thibault et al 1998;Foster et al 2001) and neurotransmitter and receptor functions, including NMDA receptor changes with age (Wenk and Barnes 2000), cholinergic coupling to CREB (Dineley et al 2001). More broadly, the age-related decrease in activation of CREB may be general to many signals and to cells in non-neural as well as neural tissues (e.g., Kunieda et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Aged rats display decreased basal forebrain and hippocampus CREB-DNA binding (Asanuma et al 1996). Expression of phosphorylated CREB (pCREB) appears to be reduced in the hippocampus of aged rats (Foster et al 2001;Brightwell et al 2004;Kudo et al 2005; but see also Monti et al 2005). Also, aged rats with poor spatial memory have hippocampal CREB levels lower than those of aged rats with good spatial memory (Brightwell et al 2004).…”

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confidence: 99%

Rapid forgetting of social transmission of food preferences in aged rats: Relationship to hippocampal CREB activation

Countryman¹,

Gold²

2007

Learn. Mem.

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A major characteristic of age-related changes in memory in rodents is an increase in the rate of forgetting of new information, even when tests given soon after training reveal intact memory. Interference with CREB functions similarly results in rapid decay of memory. Using quantitative immunocytochemistry, the present experiment examined the number of CREB-and pCREB-immunoreactive neurons in three regions of the dorsal and ventral hippocampus (dentate gyrus, CA3, and CA1) as a function of age and training. Rats were trained in a social transmission of food preference task. Using different food pairings, memory was tested in each rat immediately and 1, 2, 3, and 7 d later. Both young and old rats had intact and comparable memory scores at the immediate and 24-h tests, but old rats exhibited more rapid forgetting thereafter relative to that of young rats. The main findings were that training resulted in large increases in the number of pCREB-immunoreactive cells throughout the hippocampus in both young and aged rats. However, particularly in the ventral hippocampus, the training-elicited increase in pCREB-positive neurons was significantly lower in old than in young rats. Based on Western blot analyses in a separate set of rats, CREB levels were not responsive to training but were lower in the ventral hippocampus of old rats than of young rats. The present findings suggest that lower activation of CREB after training may contribute to the rapid forgetting seen in aged rats.Rats and mice exhibit age-related impairments in learning and memory on many tasks. Often, the impairments can be characterized in terms of rapid forgetting, in which aged rats and mice have relatively comparable learning and memory on tests soon after training, but poor memory at later times after training (Barnes and McNaughton 1985;

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Calcineurin Links Ca²⁺Dysregulation with Brain Aging

Cited by 199 publications

References 64 publications

Signal Transducer and Activator of Transcription 3 (STAT3) Degradation by Proteasome Controls a Developmental Switch in Neurotrophin Dependence

Signal Transducer and Activator of Transcription 3 (STAT3) Degradation by Proteasome Controls a Developmental Switch in Neurotrophin Dependence

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

Rapid forgetting of social transmission of food preferences in aged rats: Relationship to hippocampal CREB activation

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Calcineurin Links Ca2+Dysregulation with Brain Aging

Cited by 199 publications

References 64 publications

Signal Transducer and Activator of Transcription 3 (STAT3) Degradation by Proteasome Controls a Developmental Switch in Neurotrophin Dependence

Signal Transducer and Activator of Transcription 3 (STAT3) Degradation by Proteasome Controls a Developmental Switch in Neurotrophin Dependence

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

Rapid forgetting of social transmission of food preferences in aged rats: Relationship to hippocampal CREB activation

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Calcineurin Links Ca²⁺Dysregulation with Brain Aging