Adult mouse astrocytes degrade amyloid-β in vitro and in situ
Abstract
Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.
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Cultured adult astrocytes can migrate to and degrade amyloid plaques in brain slices from aged APP transgenic mice.
“In 2003, Wyss-Coray et al. (41) demonstrated that cultured adult astrocytes can migrate to and degrade amyloid plaques in brain slices from aged APP transgenic mice.”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [41]
Astrocytes are involved in the clearance of Aβ through the BBB via the AQP4 channels expressed in their end feet and are also able to phagocytose amyloid.
“astrocytes are involved in the clearance of Aβ through the BBB via the AQP4 channels expressed in their end feet and are also able to phagocytose amyloid [6, 34, 35].”
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 [6]
In vitro, the ability of astrocytes to take up amyloid was restricted to adult astrocytes.
“Several studies have shown that astrocytes are capable of taking up amyloid peptides (Funato et al., 1998; Matsunaga et al., 2003; Nagele et al., 2003; Lasagna-Reeves and Kayed, 2011), and in vitro this ability was restricted to adult astrocytes (al-Ali and al-Hussain, 1996; Wyss-Coray et al., 2003; Koistinaho et al., 2004; Pihlaja et al., 2008).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Wyss-Coray et al., 2003
Phagocytosis ability of astrocytes is dependent on mouse age; only mature astrocytes cultured from adult, but not neonatal, mice are able to phagocytose and degrade Aβ, reducing Aβ plaques.
“It has been reported that the phagocytosis ability of astrocytes is dependent on mouse age.Only mature astrocytes cultured from adult, but not neonatal, mice was able to phagocytose and degrade Aβ, reducing Aβ plaques (Wyss-Coray et al., 2003;Koistinaho et al., 2004).”
From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Wyss-Coray et al., 2003
Only mature astrocytes from adult mice, but not neonatal astrocytes, are capable of phagocytosing Aβ plaques.
“It has been demonstrated that only mature astrocytes from adult mice, but not neonatal astrocytes, are capable of phagocytosing Aβ plaques (Wyss-Coray et al., 2003;Koistinaho et al., 2004).”
From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Wyss-Coray et al., 2003
Accumulation of reactive astrocytes surrounding Aβ plaques is one of the earliest pathological features in Alzheimer's disease.
“Specifically, the accumulation of reactive astrocytes surrounding Aβ plaques is one of the earliest pathological features in AD (Wyss-Coray et al., 2003;Carter et al., 2012).”
From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Wyss-Coray et al., 2003
Reactive astrocytes have been reported to phagocytose and degrade Aβ, reducing Aβ plaque burden in the brain.
“reactive astrocytes have been reported to phagocytose and degrade Aβ, reducing Aβ plaque burden in the brain (Wyss-Coray et al., 2003;Koistinaho et al., 2004;Kraft et al., 2013;Gomez-Arboledas et al., 2018;Preman et al., 2021)”
From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Wyss-Coray et al., 2003
In the context of neurodegeneration, astrocytes take up aggregate-prone MAPT/tau, amyloid beta (Aβ) and SNCA (synuclein alpha), and degrade these proteins through autophagy.
“In the context of neurodegeneration, astrocytes take up aggregate-prone MAPT/tau, amyloid beta (Aβ) and SNCA (synuclein alpha), and degrade these proteins through autophagy [407–412].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [409]
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- Authors
- Wyss-Coray, T., Loike, J. D., Brionne, T. C., Lu, E., Anankov, R., Yan, F., Silverstein, S. C., & Husemann, J.
- Affiliations
- Columbia University (US)
- Stanford Medicine (US)
- Gladstone Institutes (US)
- Corresponding author
- Husemann, Jens
- Venue
- Nature Medicine
- Published
- 2003-03-03
- Volume
- 9
- Issue
- 4
- Pages
- 453-457
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2010476270
- Cited by
- 909
- References
- 24
- Citations by year
- 2026: 25 · 2025: 35 · 2024: 34 · 2023: 32 · 2022: 33 · 2021: 45 · 2020: 52 · 2019: 34 · 2018: 52 · 2017: 52 · 2016: 51 · 2015: 46 · 2014: 53 · 2013: 40 · 2012: 53
- FWCI
- 19.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Harvard University
- National Institutes of Health (1r01ag015871-01a1, 5r01ag019772-04)
- National Institute on Aging (AG08702, AG19772, P50AG008702, AG15871)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta, astrocytes, Alzheimer's disease, amyloid beta degradation, astrocyte migration, MCP-1, amyloid plaques, in situ degradation
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Cell Movement, Peptide Fragments, Amyloid beta-Peptides, Chemokine CCL2, Mice
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