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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Using homozygous human APOE knock-in mice, previous work demonstrated that APOE4 promotes Aβ aggregation and impairs its clearance relative to APOE3.
“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]
The Abstract and Discussion report that apoE4 impairs Aβ clearance from mouse brain more than apoE3. The Introduction describes greater Aβ fibrillogenesis with apoE4 than apoE3, but cites earlier mouse-model studies for that finding; this paper does not demonstrate aggregation in homozygous human APOE knock-in mice. Its Methods describe clearance experiments in C57BL/6 mice and apoE protein prepared from astrocytes derived from knock-in mice. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE exerts toxic effects on the cerebrovascular system and neurons and influences Aβ clearance, amyloid deposition, and tau-related neurodegeneration in an allele-dependent manner APOE4 > APOE3 > APOE2.
“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]
The Results report that apoE4 slows clearance across the mouse blood–brain barrier more than apoE3 or apoE2, and the Discussion describes isoform-dependent Aβ accumulation. The paper does not establish the claim’s strict APOE4 > APOE3 > APOE2 ordering for Aβ clearance: it groups apoE3 and apoE2 together. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIncreased rate of soluble Aβ clearance across the BBB has been experimentally confirmed in the setting of the APOE ε2 allele.
“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]
The Results report faster BBB clearance of Aβ complexed with apoE2 than with apoE4 in mice. But apoE2 still reduced clearance relative to free Aβ: about 38% of lipid-poor apoE2–Aβ40 cleared at 90 minutes, versus more than 85% of free Aβ40. The experiment tested apoE isoforms and their Aβ complexes, not clearance in people carrying the APOE ε2 allele. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLRP1 binds APOE2 and APOE3 as well as APOE2-Aβ and APOE3-Aβ complexes at the abluminal side of the blood-brain barrier, mediating their efflux from brain to blood.
“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]
APOE4 compared with APOE3 and APOE2 diminishes Aβ clearance across the BBB.
“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]
In animal models, APOE4 compared with APOE3 and APOE2 leads to impaired clearance of Aβ across the BBB and early BBB breakdown and transporters' dysregulation.
“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]
Aβ bound to apoE4 is cleared more slowly than when Aβ is complexed to apoE3 or apoE2.
“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]
Several studies demonstrated that apoE isoforms can differentially affect Aβ clearance.
“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
ApoE regulates both extracellular and intracellular Aβ clearance in the brain.
“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
ApoE regulates Aβ clearance in the brain.
“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
Aβ complexed to apoE2 and apoE3 is cleared out of the brain at a significantly faster rate than Aβ complexed to apoE4.
“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 brain to blood clearance of lipidated apoE4 in the mouse brain is significantly lower than the clearance of apoE3 and apoE2.
“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
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.
“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
Aβ-ApoE2 and Aβ-ApoE3 complexes are cleared by the blood brain barrier at a substantially higher rate than Aβ-ApoE4 complexes.
“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]
Levels of apoE in human cerebrospinal fluid display a genotype-dependent pattern similar to the pattern in plasma.
“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]
The Results (page unavailable) compare the appearance of injected apoE isoforms in mouse CSF and plasma; they do not report apoE levels in human CSF by genotype. Searches for human CSF concentrations and a genotype-dependent pattern matching plasma found no passage addressing that claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredMurine interstitial fluid was observed to have genotype-dependent apoE levels similar to the pattern in cerebrospinal fluid.
“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]
The Results (page unavailable) describe clearance of apoE isoforms experimentally microinfused into mouse brain interstitial fluid, including their appearance in CSF. They do not report genotype-dependent apoE levels in murine interstitial fluid or compare those levels with a genotype-dependent CSF pattern. I searched for endogenous apoE concentrations and genotype comparisons in both compartments. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Self-citationLow levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance
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Self-citation
- 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
- Health Sciences › Medicine › Physiology › 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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