ApoE Promotes the Proteolytic Degradation of Aβ
Open accessAbstract
Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in Abeta homeostasis. We report that ApoE plays a role in facilitating the proteolytic clearance of soluble Abeta from the brain. The endolytic degradation of Abeta peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Abeta degradation extracellularly by insulin-degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Abeta degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Abeta degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Abeta load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a mechanism through which ApoE facilitates the clearance of Abeta from the brain and suggest that LXR agonists may represent a novel therapy for AD.
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APOE3 promotes enzyme-mediated degradation of Aβ in microglia more efficiently than APOE4.
“APOE3 promotes enzyme-mediated degradation of A 𝛃 in microglia more efficiently than APOE4 (295), suggesting the APOE and microglia play a role in the innate immune response in AD (368).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [295]
ApoE is tightly connected to the turnover of Aβ1-42, since it plays a critical role in the normal proteolytic clearance of Aβ1-42.
“In this regard, ApoE is indeed tightly connected to the turnover of Ab 1 -42 , since it plays a critical role in the normal proteolytic clearance of Ab 1 -42 (14).”
From SUCLG2 identified as both a determinator of CSF Aβ1–42 levels and an attenuator of cognitive decline in Alzheimer's disease (2014) · cites this paper as [14]
Human apoE isoforms differed in their ability to facilitate neprilysin-mediated degradation of Aβ42 within microglia, with apoE4 being the least effective compared to apoE2 or apoE3.
“One recent in vitro study found that human apoE isoforms differed in their ability to facilitate neprilysin-mediated degradation of Aβ42 within microglia, with apoE4 being the least effective in facilitating Aβ degradation compared to apoE2 or apoE3 (60).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [60]
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 Jiang et al., 2008
Activation of Lxr increases mouse apoE and decreases Aβ levels.
“In addition, several studies have shown that activation of Lxr increases mouse apoE and decreases Aβ levels (Jiang et al., 2008).”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Jiang et al., 2008
LXR agonist treatment alleviates AD-like pathology in mouse models of amyloidosis, possibly by inducing Abca1 expression.
“LXR agonist treatment alleviates AD-like pathology in mouse models of amyloidosis, possibly by inducing Abca1 expression (29, 43–48).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [29]
ABCA1 decreases Aβ levels by promoting extracellular Aβ clearance in both neurons and glial cells.
“In addition to its role in A secretion, ABCA1 has been also shown to decrease A levels by promoting extracellular A clearance in both neurons and glial cells (Jiang et al., 2008;Kim et al., 2012).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Jiang et al., 2008
Extracellular Aβ degradation by proteases, such as insulin-degrading enzyme, is influenced by the lipidation status of ApoE.
“A previous report demonstrated that extracellular A degradation by proteases, such as insulin-degrading enzyme, is influenced by the lipidation status of ApoE (Jiang et al., 2008).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Jiang et al., 2008
ApoE lipidation by ABCA1 is critical for Aβ clearance.
“ApoE lipidation by ABCA1 is critical for A clearance (Jiang et al., 2008;Kim et al., 2012).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Jiang et al., 2008
ABCA1 is required for the effective clearance of Aβ by neuronal and glial cells.
“we and others have shown that ABCA1 is required for the effective clearance of A by neuronal and glial cells”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Jiang et al., 2008
A recent in vitro study demonstrated that the presence of fully lipidated apoE is required for effective degradation of Aβ in microglia.
“A recent in vitro study demonstrated that the presence of fully lipidated apoE is required for effective degradation of Aβ in microglia (Jiang et al., 2008; Terwel et al., 2011).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Jiang et al., 2008
Microglia migrate to amyloid plaques and may alter plaque growth dynamics in transgenic mouse models of AD.
“More recent studies in transgenic mouse models of AD have shown that microglia migrate to amyloid plaques and may alter plaque growth dynamics (9–12).”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [10]
ABCA1-mediated lipidation of apoE may play a key role in facilitating Aβ degradation by Aβ-degrading enzymes.
“ABCA1-mediated lipidation of apoE may play a key role in facilitating Aβ degradation by Aβ-degrading enzymes (Jiang et al., 2008).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Jiang et al., 2008
Treatment of several AD Tg mice models with liver X receptor or retinoid X receptor agonists, which upregulate ApoE expression and enhance its lipidation status, resulted in reduction of Aβ plaque load through enhancing clearance of Aβ by glial cells.
“In addition, treatment of several AD Tg mice models with liver X receptor or retinoid X receptor agonists, which upregulate ApoE expression and enhance its lipidation status, resulted in reduction of Ab plaque load through enhancing clearance of Ab by glial cells.43,44”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [43]
Published data indicate that the ApoE/Aβ interaction may result in multidirectional effects that may promote Aβ degradation by nonneuronal cells while enhancing Aβ accumulation in neurons.
“These published data indicate that the ApoE/Ab interaction may result in multidirectional effects that may promote Ab degradation by nonneuronal cells 43,44 while enhancing Ab accumulation in neurons.”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [43]
Short-term administration of LXR agonists TO901317 and GW3965 to 5-month-old preplaque Tg2576 mice improved fear conditioning.
“Short-term administration of LXR agonists TO901317 and GW3965 to 5-month-old preplaque Tg2576 mice improved fear conditioning (Riddell et al., 2007;Jiang et al., 2008)”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Jiang et al., 2008
Long-term treatment with GW3965 reduced plaque formation by 50% in aged Tg2576 mice.
“Long-term treatment with GW3965 has been shown to reduce plaque formation by 50% in aged Tg2576 mice (Jiang et al., 2008).”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Jiang et al., 2008
The LXR agonist GW3965 stimulates degradation of soluble Aβ in astroglial and microglial cultures dependent on ApoE and its lipidation status.
“Previously, it has been observed that the LXR agonist GW3965 stimulates degradation of soluble A in astroglial and microglial cultures dependent on ApoE and its lipidation status (Jiang et al., 2008).”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Jiang et al., 2008
apoE-containing HDL particles facilitate the proteolytic degradation of soluble Aβ.
“Importantly, apoE-containing HDL particles facilitate the proteolytic degradation of soluble Aβ (sAβ) (Jiang 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 Jiang et al., 2008
Astrocytes have the capacity to take up sAβ and degrade it in an apoE-dependent manner, similar to microglia.
“We report that astrocytes have the capacity to take up sAβ and degrade it in an apoE-dependent manner, similar to microglia (Figs. 1, 2; Jiang 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 Jiang et al., 2008
ApoE facilitates proteolysis of soluble Aβ peptides both in the interstitial fluid and intracellularly by microglia through the actions of IDE and neprilysin, respectively.
“We have previously documented that apoE acts to facilitate the proteolysis of soluble Aβ peptides both in the interstitial fluid and intracellularly by microglia through the actions of IDE and neprilysin, respectively (Jiang 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 Jiang et al., 2008
ApoE has anti-inflammatory and Aβ-metabolizing effects.
“Lipidated ApoE has anti-inflammatory effects and promotes Aβ metabolism (12)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [12]
Administration of RXR or LXR agonists reduces Aβ aggregation and restores cognitive function in AD mouse model.
“the administration of RXR or LXR agonists reduces Aβ aggregation and restores cognitive function in AD mouse model (11, 12)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [12]
Lipidated ApoE has anti-inflammatory effects and promotes Aβ metabolism.
“Lipidated ApoE has anti-inflammatory effects and promotes Aβ metabolism (12)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [12]
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 Jiang et al., 2008
ABCA1 affects Aβ clearance via apoE.
“suggesting that ABCA1 affects Aβ clearance via apoE (Jiang et al., 2008).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Jiang et al., 2008
Fully lipidated apoE is necessary for effective degradation of Aβ in microglia.
“A recent in vitro study demonstrated that the presence of fully lipidated apoE was necessary for effective degradation of Aβ in microglia, suggesting that ABCA1 affects Aβ clearance via apoE (Jiang et al., 2008).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Jiang et al., 2008
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Neuroinflammation in Alzheimer's disease
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Self-citationApolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
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Self-citationThe amyloid state and its association with protein misfolding diseases.
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“mediated degradation of Aβ42 within microglia, with apoE4 being the least effective in facilitating Aβ degradation compared to apoE2 or apoE3 (60).”
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ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models
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Self-citationAlzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta
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<i>APOE</i> predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging
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Self-citationapoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
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The role of microglia in amyloid clearance from the AD brain
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Self-citationApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
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Self-citationAmyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease
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“…pathway Our previous work and that of others has demonstrated a role for LXR activation in stimulating the production of apoE and facilitating the proteolytic degradation of A (Koldamova et al., 2005a; Riddell et al., 2007; Jiang et al., 2008; Donkin et al., 2010; Fitz et al., 2010).”
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Self-citationAstrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition
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- Authors
- Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., Richardson, J. C., Smith, J. D., Comery, T. A., Riddell, D., Holtzman, D. M., Tontonoz, P., & Landreth, G. E.
- Affiliations
- Case Western Reserve University (US)
- Howard Hughes Medical Institute (US)
- Cleveland Clinic (US)
- GlaxoSmithKline (United Kingdom) (GB)
- Wyeth (US)
- Washington University in St. Louis (US)
- Corresponding author
- Landreth, Gary E.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 58
- Issue
- 5
- Pages
- 681-693
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2493297
- OpenAlex
- W1994554610
- Cited by
- 876
- References
- 74
- Citations by year
- 2026: 15 · 2025: 34 · 2024: 33 · 2023: 37 · 2022: 35 · 2021: 42 · 2020: 42 · 2019: 47 · 2018: 46 · 2017: 50 · 2016: 57 · 2015: 60 · 2014: 70 · 2013: 70 · 2012: 56
- FWCI
- 41.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (R01AG013956, R01AG020202, AG020202, R01AG030482, F32AG24031, F32AG024031, R37AG013956, AG13956)
- National Heart, Lung, and Blood Institute (HL3 0568, P01HL030568, R01HL066082, R01HL066088, HL66088)
- 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, neprilysin, insulin-degrading enzyme, microglia, APOE isoforms, lipid modification, liver X receptor, GW3965, Tg2576 mice, Alzheimer's disease, memory impairment
- MeSH terms
- Liver X Receptors, Aging, Alzheimer Disease, Animals, Animals, Newborn, Apolipoproteins E, Behavior, Animal, Benzoates, Benzylamines, Brain, Cells, Cultured, Disease Models, Animal, DNA-Binding Proteins, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay, Memory, Mice, Inbred C57BL, Mice, Transgenic, Peptide Fragments, Time Factors, Amyloid beta-Peptides, Microglia, Receptors, Cytoplasmic and Nuclear, ATP-Binding Cassette Transporters, Mice, Orphan Nuclear Receptors, Plaque, Amyloid, ATP Binding Cassette Transporter 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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