title: Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer's disease.
abstract: Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific Gfa2 promoter to target hippocampal astrocytes in APP/PS1 mice. AAV-Gfa2 vectors drove the expression of VIVIT, a peptide that interferes with the immune/inflammatory calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway, shown by our laboratory and others to orchestrate biochemical cascades leading to astrocyte activation. After several months of treatment with Gfa2-VIVIT, APP/PS1 mice exhibited improved cognitive and synaptic function, reduced glial activation, and lower amyloid levels. The results confirm a deleterious role for activated astrocytes in AD and lay the groundwork for exploration of other novel astrocyte-based therapies.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Furman
authors.forename: Diana M
authors.initials: DM
authors.lastname: Sama
authors.forename: John C
authors.initials: JC
authors.lastname: Gant
authors.forename: Tina L
authors.initials: TL
authors.lastname: Beckett
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Norris
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D001362:Avoidance Learning / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018014:Gene Transfer Techniques; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D065095:Calcineurin Inhibitors; D050778:NFATC Transcription Factors; D009842:Oligopeptides; C121611:VIVIT peptide