title: 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 Ca2+-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.
authors.affiliation: Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky 40536, USA. cnorr2@uky.edu
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Norris
authors.forename: Inga
authors.initials: I
authors.lastname: Kadish
authors.forename: Eric M
authors.initials: EM
authors.lastname: Blalock
authors.forename: Kuey-Chu
authors.initials: KC
authors.lastname: Chen
authors.forename: Veronique
authors.initials: V
authors.lastname: Thibault
authors.forename: Nada M
authors.initials: NM
authors.lastname: Porter
authors.forename: Philip W
authors.initials: PW
authors.lastname: Landfield
authors.forename: Susan D
authors.initials: SD
authors.lastname: Kraner
mesh_terms: D000256:Adenoviridae / Q000502:physiology; D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019703:Calcineurin / Q000502:physiology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D005822:Genetic Vectors / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis / Q000379:methods; D053764:Presenilin-1; D051381:Rats; D011916:Rats, Inbred F344; D015854:Up-Regulation
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D053764:Presenilin-1; D016572:Cyclosporine; D019703:Calcineurin