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.
Document Type
Article
Publication Date
11-14-2012
Digital Object Identifier (DOI)
http://dx.doi.org/10.1523/JNEUROSCI.2323-12.2012
Repository Citation
Furman, Jennifer L.; Sama, Diana M.; Gant, John C.; Beckett, Tina L.; Murphy, M. Paul; Bachstetter, Adam D.; Van Eldik, Linda J.; and Norris, Christopher M., "Targeting Astrocytes Ameliorates Neurologic Changes in a Mouse Model of Alzheimer's Disease" (2012). Pharmacology and Nutritional Sciences Faculty Publications. 1.
https://uknowledge.uky.edu/pharmacol_facpub/1
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Medical Biochemistry Commons, Medical Neurobiology Commons, Medical Pharmacology Commons, Neuroscience and Neurobiology Commons, Pharmacology, Toxicology and Environmental Health Commons
Notes/Citation Information
Published in The Journal of Neuroscience, v. 32, no. 46, p. 16129-16140.
Copyright of all material published in The Journal of Neuroscience remains with the authors. The authors grant the Society for Neuroscience an exclusive license to publish their work for the first 6 months. After 6 months the work becomes available to the public to copy, distribute, or display under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license.