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

Abstract

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.

Overactivation of calcineurin induced by amyloid-beta and prion proteins

“…The involvement of CaN in the neurodegenerative process and memory impairment in AD and PRE remains a controversial issue (Wang et al, 1999;Norris et al, 2005;Biasini et al, 2006;Dineley et al, 2007). In a previous study we demonstrated that Ab and PrP peptides trigger a caspase-3-dependent apoptotic neuronal death pathway, involving CaN and cyt c release from mitochondria (Agostinho and Oliveira, 2003).…”

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

“…37 Ab species, particularly oligomers, can activate both astrocytes and microglia. 38,39 Recently, genetic data 40e44 corroborated by experimental studies 45e49 have directly implicated microglia in the pathogenesis of AD through mechanisms that involve either Ab phagocytosis or the secretion of proinflammatory cytokines. Similarly, reactive Figure 4 The association between SMI312 þ dystrophic neurites per plaque and symptom duration is stronger at initial stages.…”

Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease

“…Recently, the activation phenotype of both astrocytes and microglial cells was reported to be largely mediated through the calcineurin-nuclear factor of activated T cells pathway. 48,49 Fibrillar and particularly oligomeric A␤ can aberrantly activate this molecular signaling pathway in glial cells 48,50 and neurons, causing the morphological triad of dystrophic neurites, dendritic simplification, and loss of dendritic spines, subsequently leading to cognitive impairment. [51][52][53] More important, Food and Drug Administration-approved and available calcineurin inhibitors, Figure 7.…”