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apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
Open accessAbstract
Neurotoxic amyloid beta peptide (Abeta) accumulates in the brains of individuals with Alzheimer disease (AD). The APOE4 allele is a major risk factor for sporadic AD and has been associated with increased brain parenchymal and vascular amyloid burden. How apoE isoforms influence Abeta accumulation in the brain has, however, remained unclear. Here, we have shown that apoE disrupts Abeta clearance across the mouse blood-brain barrier (BBB) in an isoform-specific manner (specifically, apoE4 had a greater disruptive effect than either apoE3 or apoE2). Abeta binding to apoE4 redirected the rapid clearance of free Abeta40/42 from the LDL receptor-related protein 1 (LRP1) to the VLDL receptor (VLDLR), which internalized apoE4 and Abeta-apoE4 complexes at the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as Abeta-apoE2 and Abeta-apoE3 complexes were cleared at the BBB via both VLDLR and LRP1 at a substantially faster rate than Abeta-apoE4 complexes. Astrocyte-secreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their complexes with Abeta were cleared at the BBB by mechanisms similar to those of their respective lipid-poor isoforms but at 2- to 3-fold slower rates. Thus, apoE isoforms differentially regulate Abeta clearance from the brain, and this might contribute to the effects of APOE genotype on the disease process in both individuals with AD and animal models of AD.
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In the citing paper
“Using homozygous human APOE knock-in mice, previous work demonstrated that APOE4 promotes A β aggregation and impairs its clearance relative to APOE3 34,38,39 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [39]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE exerts toxic effects on the cerebrovascular system (694) and neurons (383, 384) and influences A 𝛃 clearance (60, 64, 98, 135, 256, 266, 278, 294, 315, 693), amyloid deposition (39, 256, 258, 266, 278, 314, 518, 612), and tau-related neurodegeneration (533) in an allele-dependent manner APOE4 > APOE3 > APOE2 .”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [135]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In fact increased rate of soluble Aβ clearance across the BBB has been experimentally confirmed in the setting of the APOE ε2 allele [32, 48].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [48]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Notably, the contribution of ISF bulk flow to total Aβ clearance was minimal (Fig. 1B), consistent with previous studies (14, 15, 20).”
From Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis (2012) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“When injecting low nM [ 125 I] Aβ 1-42 concentrations in mice, we found no significant amount of radioactivity in the CSF, showing that the small amounts of injected Aβ are rapidly cleared via the BBB and that a minor amount of injected Aβ is cleared via bulk flow as also observed by previous studies (8,11,12).”
From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [12]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Moreover, with an endocytosis rate up to 16 times faster than that of other Aβ receptors, such as VDLDR or LDLR (12,35), LRP1 may outperform other receptors in Aβ clearance, especially at higher concentrations.”
From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Moreover, with an endocytosis rate up to 16 times faster than that of other Aβ receptors, such as VDLDR or LDLR (12,35), LRP1 may outperform other receptors in Aβ clearance, especially at higher concentrations.”
From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [12]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“LRP1 also binds APOE2 and APOE3 as well as APOE2-A 𝛃 and APOE3-A 𝛃 complexes at the abluminal side of the BBB, mediating their efflux from brain-toblood (135).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [135]
The cited source says what the claim attributes to it.
In the citing paper
“Studies in animal models support that APOE4 compared with APOE3 and APOE2 diminishes A 𝛃 clearance across the BBB (58, 135), which has been confirmed in transgenic APOE4 mice (98).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [135]
The cited source says what the claim attributes to it.
In the citing paper
“and in animal models, APOE4 compared with APOE3 and APOE2 leads to impaired clearance of A 𝛃 across the BBB (58, 98, 135) and an early BBB breakdown and transporters' dysregulation (9, 60, 85, 437).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [135]
The cited source says what the claim attributes to it.
In the citing paper
“A recent study wherein apoE/Aβ complexes were microinjected into wildtype mouse brain revealed that Aβ bound to apoE4 is cleared more slowly than when Aβ is complexed to apoE3 or apoE2 (56).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [56]
The cited source says what the claim attributes to it.
In the citing paper
“Several studies demonstrated that apoE isoforms can differentially affect Aβ clearance (Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011).”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Deane et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, recent studies strongly suggest that apoE regulates both extracellular and intracellular Aβ clearance in the brain (Bell et al., 2007; Deane et al., 2008; DeMattos et al., 2004; Jiang et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Deane et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, apoE has been shown to regulate Aβ clearance in the brain (Bell et al., 2007; Deane et al., 2008; DeMattos et al., 2004; Jiang et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Deane et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, Aβ complexed to apoE2 and apoE3 is cleared out of the brain at a significantly faster rate than Aβ complexed to apoE4 (Deane et al., 2008).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Deane et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“A recent study has shown that the brain to blood clearance of lipidated apoE4 in the mouse brain is significantly lower than the clearance of apoE3 and apoE2 (Deane et al., 2008).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Deane et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“Accumulating recent evidence strongly suggests that when human apoE is complexed with Aβ, the brain to blood clearance of Aβ is actually decreased compared to that of free Aβ (Bell et al., 2007; Deane et al., 2008; Ito et al., 2007).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Deane et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“In animal models, Aβ–ApoE2 and Aβ–ApoE3 complexes are cleared by the blood brain barrier (BBB) at a substantially higher rate than Aβ–ApoE4 complexes [23].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [23]
The cited source says what the claim attributes to it.
In the citing paper
“These results suggest the LDLR overexpression in neurons and astrocytes (18) likely increases BBB-mediated Aβ clearance through an indirect mechanism involving other apoE receptors at the BBB, such as LRP1—a receptor shown to directly mediate Aβ clearance across the BBB (14, 15, 26).”
From Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis (2012) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“our work strongly suggests that LDLR influences Aβ metabolism by affecting its clearance from the brain into blood, a mechanism previously suggested only for LRP1 and VLDLR (13–15, 26).”
From Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis (2012) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“Although low-density lipoprotein receptor-related protein 1 (LRP1) has been well characterized for its role in BBB-mediated Aβ clearance (13–15), whether LDLR plays a role in Aβ clearance across the BBB is unclear.”
From Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis (2012) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“ApoE has been shown to impede the clearance of Aβ from brain ISF (13, 15, 43); therefore, it is likely that the reduction of apoE levels with LDLR overexpression facilitates greater ISF Aβ clearance across the BBB.”
From Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis (2012) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“Recent studies suggest that transport across the BBB is a major elimination route for brain Aβ (8,11,12,15).”
From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [12]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“However, levels of apoE in human cerebrospinal fluid do display genotype-dependent pattern similar to the pattern in plasma, further murine interstitial fluid was observed to have genotype-dependent apoE levels similar to the pattern in cerebrospinal fluid [105,112,113].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [113]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“However, levels of apoE in human cerebrospinal fluid do display genotype-dependent pattern similar to the pattern in plasma, further murine interstitial fluid was observed to have genotype-dependent apoE levels similar to the pattern in cerebrospinal fluid [105,112,113].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [113]
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“The rapid A clearance from the brain observed here is due to the rapid transport of A through the blood– brain barrier and the interstitial fluid drainage pathways (Deane et al., 2008).”
BackgroundZhao, L., Gottesdiener, A. J., Parmar, M., Li, M., Kaminsky, S. M., Chiuchiolo, M. J., Sondhi, D., Sullivan, P. M., Holtzman, D. M., Crystal, R. G., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.04.020 · Cited by 107
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Metadata
- Authors
- Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., Holtzman, D. M., & Zlokovic, B. V.
- Affiliations
- University of Rochester Medicine (US)
- Washington University in St. Louis (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2008-12-01
- Volume
- 118
- Issue
- 12
- Pages
- 4002-4013
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2582453
- OpenAlex
- W2138992210
- Cited by
- 771
- References
- 71
- Citations by year
- 2026: 35 · 2025: 39 · 2024: 51 · 2023: 40 · 2022: 42 · 2021: 48 · 2020: 47 · 2019: 47 · 2018: 35 · 2017: 49 · 2016: 38 · 2015: 51 · 2014: 48 · 2013: 41 · 2012: 52
- FWCI
- 24.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Institutes of Health (R37 NS34467, NS34467, AG13956, R37 AG13956)
- National Institute on Aging (R37AG023084, R37AG13956, R37AG013956)
- National Institute of Neurological Disorders and Stroke (R37NS034467, R37NS34467)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE isoforms, APOE ε4, Alzheimer's disease, blood-brain barrier, LRP1, VLDLR, APOE2, APOE3, amyloid accumulation
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Blood-Brain Barrier, Disease Models, Animal, Humans, Male, Receptors, LDL, Amyloid beta-Peptides, Protein Isoforms, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Mice, Apolipoprotein E3, Apolipoprotein E4
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