Calcium dysregulation and neuroinflammation: Discrete and integrated mechanisms for age-related synaptic dysfunction

Sama, Diana M.; Norris, Christopher M.

doi:10.1016/j.arr.2013.05.008

Cited by 101 publications

(69 citation statements)

References 281 publications

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“…For instance, CN signaling pathways help drive the production of numerous immune factors, including tumor necrosis factor and other cytokines, which are implicated in chronic neuroinflammation [14, 75–77] and widely regarded as causal factors of synaptic decline in animal models of aging, injury, and AD [74, 78, 79]. Synaptic function is also strongly modulated by a variety of releasable factors ( e.g.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function

Pleiss¹,

Sompol²,

Kraner³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Mounting evidence suggests that astrocyte activation, found in most forms of neural injury and disease, is linked to the hyperactivation of the protein phosphatase calcineurin. In many tissues and cell types, calcineurin hyperactivity is the direct result of limited proteolysis. However, little is known about the proteolytic status of calcineurin in activated astrocytes. Here, we developed a polyclonal antibody to a high activity calcineurin proteolytic fragment in the 45–48 kDa range (ΔCN) for use in immunohistochemical applications. When applied to postmortem human brain sections, the ΔCN antibody intensely labeled cell clusters in close juxtaposition to amyloid deposits and microinfarcts. Many of these cells exhibited clear activated astrocyte morphology. The expression of ΔCN in astrocytes near areas of pathology was further confirmed using confocal microscopy. Multiple NeuN-positive cells, particularly those within microinfarct core regions, also labeled positively for ΔCN. This observation suggests that calcineurin proteolysis can also occur within damaged or dying neurons, as reported in other studies. When a similar ΔCN fragment was selectively expressed in hippocampal astrocytes of intact rats (using adeno-associated virus), we observed a significant reduction in the strength of CA3-CA1 excitatory synapses, indicating that the hyperactivation of astrocytic calcineurin is sufficient for disrupting synaptic function. Together, these results suggest that proteolytic activation of calcineurin in activated astrocytes may be a central mechanism for driving and/or exacerbating neural dysfunction during neurodegenerative disease and injury.

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Section: Discussionmentioning

confidence: 99%

Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function

Pleiss¹,

Sompol²,

Kraner³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Surely, at least some of these beneficial effects are attributable to direct inhibition of deleterious neuronal CN signaling pathways, which have been shown to play important roles in neuronal degeneration and altered synaptic function (e.g., see [105-107]). However, what about the impact of glial CN signaling?…”

Section: Reviewmentioning

confidence: 99%

Calcineurin and glial signaling: neuroinflammation and beyond

Furman

Norris

2014

J Neuroinflammation

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Similar to peripheral immune/inflammatory cells, neuroglial cells appear to rely on calcineurin (CN) signaling pathways to regulate cytokine production and cellular activation. Several studies suggest that harmful immune/inflammatory responses may be the most impactful consequence of aberrant CN activity in glial cells. However, newly identified roles for CN in glutamate uptake, gap junction regulation, Ca2+ dyshomeostasis, and amyloid production suggest that CN’s influence in glia may extend well beyond neuroinflammation. The following review will discuss the various actions of CN in glial cells, with particular emphasis on astrocytes, and consider the implications for neurologic dysfunction arising with aging, injury, and/or neurodegenerative disease.

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“…In fact, various studies have described age-related changes in glial activation markers including expression of proinflammatory cytokines, such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) [156][157][158]. Pro-inflammatory cytokines affect baseline synaptic activity in a variety of conditions, and they appear to mediate at least some of the detrimental effects of neuroinflammation on aging synapses [159].…”

Section: Accepted Manuscriptmentioning

confidence: 98%

Neurochemical correlation between major depressive disorder and neurodegenerative diseases

et al. 2016

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Calcium dysregulation and neuroinflammation: Discrete and integrated mechanisms for age-related synaptic dysfunction

Cited by 101 publications

References 281 publications

Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function

Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function

Calcineurin and glial signaling: neuroinflammation and beyond

Neurochemical correlation between major depressive disorder and neurodegenerative diseases

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