Astrocyte Activation and the Calcineurin/NFAT Pathway in Cerebrovascular Disease

Abstract

Calcineurin (CN) is a Ca2+/calmodulin-dependent protein phosphatase with high abundance in nervous tissue. Though enriched in neurons, CN can become strongly induced in subsets of activated astrocytes under different pathological conditions where it interacts extensively with the nuclear factor of activated T cells (NFATs). Recent work has shown that regions of small vessel damage are associated with the upregulation of a proteolized, highly active form of CN in nearby astrocytes, suggesting a link between the CN/NFAT pathway and chronic cerebrovascular disease. In this Mini Review article, we discuss CN/NFAT signaling properties in the context of vascular disease and use previous cell type-specific intervention studies in Alzheimer’s disease and traumatic brain injury models as a framework to understand how astrocytic CN/NFATs may couple vascular pathology to neurodegeneration and cognitive loss.

Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis

“…Astrocytes, identified as the largest number of cells in the central nervous system (CNS), interact with neurons in order to maintain the stability of the CNS environment [25][26][27]. In response to cerebral ischemia, astrocytes undergo hyperplasia and metabolic reserve enhancement and delayed apoptosis is observed in neurons [28][29][30]. Aberrant miRNA expression levels have been correlated with models of cerebral ischemia injury [31][32][33].…”

Secretagogin expression in the vertebrate brainstem with focus on the noradrenergic system and implications for Alzheimer’s disease

“…Calcium dysregulation triggers astrocyte activation which leads to neuroinflammation, release of synaptotoxic factors and loss of glutamate regulation which can finally culminate in neurodegeneration (Sompol and Norris 2018). Dysregulation of calcineurin signalling pathways in activated astrocytes and its interaction with the nuclear factor of activated T cells (NFATs) couple vascular pathology to neurodegeneration and cognitive loss (Kraner and Norris 2018). Calcium sensor proteins have been previously implicated in neuroprotection: dopamine neurons in the substantia nigra use calretinin to confer oestrogen’s effect to prevent cell loss (Yi et al 2016) and calretinin cooperates with the NCX1 exchanger to resist neurodegeneration (Boscia et al 2016).…”

Calcineurin

“…For this reason, the immunosuppressant drugs tacrolimus and cyclosporin are used to bind to and inhibit CaN [33]. The NFATs dephosphorylated by CaN activate transcription programs in other systems such as neurons and astrocytes [11,12], as well as the heart and skeletal muscle [13][14][15][16].…”

“…CaN has been linked with a number of proteins associated with mitochondria for quite some time [27,28,50]. For example, CaN dephosphorylates dynamin-related Table 1 Signaling processes that calcineurin plays roles in and example substrates Signaling processes/molecules Example calcineurin substrates Transcription NFATs (nuclear factors of activated T-cells) [3,4,[8][9][10][11][12][13][14][15][16] FOXO (forkhead transcription factors) [17,18] MEF2 (myocyte-specific enhancer factor 2) [13,15,16] TFEB (transcription factor EB) [12,16,18,19] Receptors and channels AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors) [20,21] NMDARs (NMDA-type ionotropic glutamate receptors) [20,21] TRESK (tandem-pore-domain weakly inward rectifying potassium channels (TWIK)-related spinal cord potassium channels) [22][23][24] NHE1 (Na+/H+ exchanger 1) [16,25,26] Mitochondria DRP1 (dynamin-related protein 1) [27] BAD (Bcl-2/Bcl-XL-antagonist, causing cell death) [28][29][30] Microtubules tau [31] MAP2 [31] protein 1 (DRP1), linking catecholamines, via calcium signaling, to mitochondrial fis...…”