Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer's disease
Open accessAbstract
The role of astrocytes in the progression of Alzheimer's disease (AD) remains poorly understood. We assessed the consequences of ablating astrocytic proliferation in 9 months old double transgenic APP23/GFAP‐TK mice. Treatment of these mice with the antiviral agent ganciclovir conditionally ablates proliferating reactive astrocytes. The loss of proliferating astrocytes resulted in significantly increased levels of monomeric amyloid‐β (Aβ) in brain homogenates, associated with reduced enzymatic degradation and clearance mechanisms. In addition, our data revealed exacerbated memory deficits in mice lacking proliferating astrocytes concomitant with decreased levels of synaptic markers and higher expression of pro‐inflammatory cytokines. Our data suggest that loss of reactive astrocytes in AD aggravates amyloid pathology and memory loss, possibly via disruption of amyloid clearance and enhanced neuroinflammation.
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Depletion of reactive astrocytes in AD mice results in increased plaque load, synaptic dysfunction and memory loss.
“Moreover, reactive astrocytes play a beneficial role in limiting AD pathology, and their depletion in AD mice results in increased plaque load, synaptic dysfunction and memory loss 51 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [51]
The Results sections on synaptic density and memory report synaptic loss and worsened spatial-memory performance after ablation of proliferating reactive astrocytes in APP23 mice. But the Results section on amyloid-β (page unavailable) explicitly reports no significant change in amyloid plaque burden measured by Thio-S staining; increased amyloid-β staining is not the same as increased plaque load. (LLM, conf=0.91)
Experimental — accuracy not yet measuredLoss of proliferating astrocytes leads to increased amyloid levels and exacerbated memory loss in the APP23 model of AD.
“We have recently shown that the loss of proliferating astrocytes leads to increased amyloid levels and exacerbated memory loss in the APP23 model of AD [17].”
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 [17]
These results reinforce the function of astrocytes regulating synapsis in AD.
“These results reinforce the function of astrocytes regulating synapsis in AD, shown by us and others [17, 43].”
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 [17]
Expression of neprilysin was decreased following astrocytic loss.
“We have demonstrated, using two different approaches, that the expression of neprilysin was decreased following astrocytic loss ([17] and present study).”
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 [17]
Reactive astrocytes play a beneficial role in limiting AD pathology.
“Moreover, reactive astrocytes play a beneficial role in limiting AD pathology, and their depletion in AD mice results in increased plaque load, synaptic dysfunction and memory loss 51 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [51]
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- Authors
- Katsouri, L., Birch, A. M., Renziehausen, A. W. J., Zach, C., Aman, Y., Steeds, H., Bonsu, A., Palmer, E. O. C., Mirzaei, N., Ries, M., & Sastre, M.
- Affiliations
- Hammersmith Hospital (GB)
- Corresponding author
- Sastre, Magdalena
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2019-12-04
- Volume
- 68
- Issue
- 5
- Pages
- 1017-1030
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC7383629
- OpenAlex
- W2993940957
- Cited by
- 81
- References
- 47
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 9 · 2023: 15 · 2022: 18 · 2021: 17 · 2020: 9
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Glia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Alzheimer's Research Trust (ART‐PG2011‐12, ART‐PPG2009B‐10)
- 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
- reactive astrocytes, Alzheimer's disease, amyloid-beta, amyloid clearance, ganciclovir, memory impairment, neuroinflammation, inflammatory cytokines, synaptic markers, astrocyte proliferation
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Disease Models, Animal, Glial Fibrillary Acidic Protein, Inflammation, Memory, Short-Term, Mice, Transgenic, Amyloid beta-Protein Precursor, Disease Progression, Cell Proliferation, Mice, Spatial Memory
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