Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides

Koistinaho, Milla; Lin, Suizhen; Wu, Xin; Esterman, Michail; Koger, Deanna; Hanson, Jeffrey; Higgs, Richard; Liu, Feng; Malkani, Seema; Bales, Kelly R; Paul, Steven M

doi:10.1038/nm1058

Cited by 571Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides

Koistinaho, Milla, Lin, Suizhen, Wu, Xin, Esterman, Michail, Koger, Deanna, Hanson, Jeffrey, Higgs, Richard, Liu, Feng +3 more·2004·Nature Medicine

DOI 10.1038/nm1058

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Abstract

We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-beta peptides (Abeta) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Abeta, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe(-/-) astrocytes do not degrade Abeta present in Abeta plaque-bearing brain sections in vitro. Coincubation with antibodies to either Apoe or Abeta, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks Abeta degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe(-/-) astrocytes do not respond to or internalize Abeta deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited Abeta species by astrocytes, a process that may be impaired in Alzheimer disease.

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Plaque-degrading activity in astrocytes is dependent on apolipoprotein E (apoE) expression.
“Moreover, this plaque-degrading activity in astrocytes was subsequently found to be dependent on apolipoprotein E (apoE) expression (42).”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [42]
In a mouse model of amyloid deposition, ApoE promotes the localization of astrocytes to plaques.
“In a mouse model of amyloid deposition, ApoE has been reported to promote the localization of astrocytes to plaques (19).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [19]
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 Koistinaho et al., 2004
Endogenous CNS-derived apoE-containing lipoprotein particles bind to Aβ and promote its clearance and degradation.
“endogenous CNS-derived apoE-containing lipoprotein particles bind to A␤ and promote its clearance and degradation (DeMattos et al., 2004;Koistinaho et al., 2004;Manelli et al., 2004;Stratman et al., 2005;Trommer et al., 2005)”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Koistinaho et al., 2004
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 Koistinaho et al., 2004

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 Koistinaho et al., 2004
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 Koistinaho et al., 2004
Two in vitro studies have demonstrated that apoE can facilitate the cellular degradation of Aβ.
“Two in vitro studies have also demonstrated that apoE can facilitate the cellular degradation of Aβ (Jiang et al., 2008; Koistinaho et al., 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Koistinaho et al., 2004
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 [407]

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Authors: Koistinaho, M., Lin, S., Wu, X., Esterman, M., Koger, D., Hanson, J., Higgs, R., Liu, F., Malkani, S., Bales, K. R., & Paul, S. M.
Affiliations: Eli Lilly (United States) (US)
Corresponding author: Paul, Steven M
ORCID: Wu, Xin
Hanson, Jeffrey
Higgs, Richard
Liu, Feng
Paul, Steven M
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2004-06-13
Volume: 10
Issue: 7
Pages: 719-726
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/nm1058
OpenAlex: W2171311951
Cited by: 571
References: 40
Citations by year: 2026: 13 · 2025: 20 · 2024: 15 · 2023: 20 · 2022: 29 · 2021: 23 · 2020: 34 · 2019: 31 · 2018: 26 · 2017: 29 · 2016: 32 · 2015: 29 · 2014: 36 · 2013: 30 · 2012: 38
FWCI: 13.59
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: Suomen Kulttuurirahasto
Saastamoisen säätiö
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: apolipoprotein E, amyloid-beta, astrocytes, amyloid beta degradation, Alzheimer's disease, amyloid plaques, rap, low-density lipoprotein receptor family, ApoE-deficient mice
MeSH terms: Animals, Apolipoproteins E, Astrocytes, Cell Aggregation, Cell Survival, Cells, Cultured, Mice, Inbred C57BL, Amyloid beta-Peptides, Low Density Lipoprotein Receptor-Related Protein-1, Mice

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Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides

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