Targeting Astrocytes Ameliorates Neurologic Changes in a Mouse Model of Alzheimer's Disease
Open accessAbstract
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.
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The consensus is that reduction in astrocyte density leads to higher amyloid levels, without changes in its aggregation or deposition.
“Therefore, it seems that the consensus is that the reduction in astrocyte density leads to higher amyloid levels, without changes in its aggregation or deposition.”
From Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease (2021) · cites this paper as [31]
The Results section on glial activation reports that Gfa2-VIVIT reduced astrocyte size but did not reduce the number of GFAP-labeled cells. The Results section on amyloid pathology reports lower Aβ levels alongside fewer and smaller amyloid deposits—not higher levels without a change in deposition. It also describes the role of neuroglia in amyloid pathology as controversial, rather than a consensus. (LLM, conf=0.91)
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Experimental — accuracy not yet measuredManipulation of reactive astrocytes has resulted in improved outcomes, worse outcomes, and no change in mouse models of AD and MS.
“For example, the manipulation of reactive astrocytes has resulted in improved outcomes38,42,43, worse35 outcomes, and no change44 in mouse models of AD and MS40,45,46.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [38]
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“Although BACE1 levels are generally far lower in glial cells relative to neurons (Vassar et al., 1999; Laird et al. 2005), the sheer abundance of astrocytes in brain may still provide a significant source for the generation of A peptides (Zhao et al., 2011).”
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(2020) · Advances in Quantum Chemistry · doi:10.1016/bs.aiq.2020.08.002 · Cited by 6 · see citing works
- Authors
- Furman, J. L., Sama, D. M., Gant, J. C., Beckett, T. L., Murphy, M. P., Bachstetter, A. D., Van Eldik, L. J., & Norris, C. M.
- Affiliations
- University of Kentucky (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-11-14
- Volume
- 32
- Issue
- 46
- Pages
- 16129-16140
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3506017
- OpenAlex
- W2106729121
- Cited by
- 313
- References
- 8
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 14 · 2023: 23 · 2022: 28 · 2021: 28 · 2020: 20 · 2019: 16 · 2018: 28 · 2017: 25 · 2016: 31 · 2015: 30 · 2014: 19 · 2013: 21
- FWCI
- 15.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by-nc-sa)
- Funders
- Pharmaceutical Research and Manufacturers of America Foundation
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- National Institutes of Health
- National Institute on Aging (P01AG005119, AG 027297, R01AG027297, RF1AG027297, AG-005119)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- astrocytes, astrocyte activation, Alzheimer's disease, ViViT, calcineurin/NFAT signaling, adeno-associated virus vectors, APP/PS1 mice, hippocampus, amyloid, neuroinflammation, cognitive function, synaptic function, glial activation, astrocyte-targeted therapy
- MeSH terms
- Dependovirus, Alzheimer Disease, Animals, Astrocytes, Avoidance Learning, Brain, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Inflammation, Mice, Transgenic, Neurons, Oligopeptides, Blotting, Western, Signal Transduction, Long-Term Potentiation, Gene Transfer Techniques, Excitatory Postsynaptic Potentials, NFATC Transcription Factors, Mice, Calcineurin Inhibitors
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