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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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In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
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 Jiang et al., 2008
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“One common hypothesis states that APOE sequesters soluble Aβ in the extracellular space resulting in cellular uptake and catabolism of this neurotoxic peptide. This hypothesis is supported by many in vitro studies (Koistinaho et al., 2004; Morikawa et al., 2005; Jiang et al., 2008).”
From The Pro-Neurotrophin Receptor Sortilin Is a Major Neuronal Apolipoprotein E Receptor for Catabolism of Amyloid-β Peptide in the Brain (2013) · cites this paper as Jiang et al., 2008
In the citing paper
“In the brain, endocytic pathways in glia cells (likely the LDL receptor) and in neurons are implicated in cellular catabolism of APOE/Aβ complexes (Koistinaho et al., 2004; Jiang et al., 2008; Holtzman et al., 2012).”
From The Pro-Neurotrophin Receptor Sortilin Is a Major Neuronal Apolipoprotein E Receptor for Catabolism of Amyloid-β Peptide in the Brain (2013) · cites this paper as Jiang et al., 2008
In the citing paper
“ApoE4 cells are less efficient in promoting intracellular A42 degradation compared with ApoE3 cells (Jiang et al., 2008).”
From ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes (2019) · cites this paper as Jiang et al., 2008
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Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
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