Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy

Bu, Guojun

doi:10.1038/nrn2620

Cited by 1,168Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy

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Bu, Guojun·2009·Nature Reviews Neuroscience

DOI 10.1038/nrn2620PMC PMC2908393

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Abstract

The vast majority of Alzheimer's disease (AD) cases are late-onset and their development is probably influenced by both genetic and environmental risk factors. A strong genetic risk factor for late-onset AD is the presence of the epsilon4 allele of the apolipoprotein E (APOE) gene, which encodes a protein with crucial roles in cholesterol metabolism. There is mounting evidence that APOE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of amyloid-beta peptide and by directly regulating brain lipid metabolism and synaptic functions through APOE receptors. Emerging knowledge of the contribution of APOE to the pathophysiology of AD presents new opportunities for AD therapy.

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RAGE plays an important role in the uptake of Aβ by microglia.
“RAGE is also reported to play an important role in the uptake of Aβ by microglia.333”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [333]
The section “ApoE and apoE receptors in Aβ clearance and aggregation” describes receptor-mediated internalization of Aβ by microglia. It identifies apoE receptors, including LRP1, LDLR and VLDLR, but does not identify RAGE or establish its role in that uptake. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
In the brain and neuronal cultures, ApoE is synthesized in astrocytes.
“In the brain and neuronal cultures, ApoE is synthesized in astrocytes.14,15”
From Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain (2013) · cites this paper as [15]
The Biochemical properties section states that astrocytes are the predominant source of ApoE in the brain and describes ApoE particles secreted by cultured astrocytes. It does not specifically establish where ApoE is synthesized in neuronal cultures, and it notes that microglia also synthesize some ApoE. Page numbers are unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
ApoE4 lowers the age of onset of Alzheimer's disease.
“lowers the age of onset [4–14]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [5]
The Introduction identifies ApoE ε4 as a major risk factor for late-onset Alzheimer’s disease and says its effect on risk is greatest between ages 60 and 70. It does not state that carriers develop Alzheimer’s at a younger age than noncarriers, so the specific age-of-onset claim goes beyond what the copy reports. (LLM, conf=0.76)
Experimental — accuracy not yet measured
ApoE is critical for brain cholesterol homeostasis and, produced primarily by astrocytes, delivers cholesterol and essential lipids to neurons by interacting with members of the LDLR family.
“ApoE, critical for brain cholesterol homeostasis and produced primarily by astrocytes, delivers cholesterol and essential lipids to neurons by interacting with members of the low-density lipoprotein receptor (LDLR) family (21).”
From APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [21]
Brain lipids transported by apoE/lipoprotein particles play critical roles in neuronal membrane homeostasis and synaptic functions.
“Brain lipids transported by apoE/lipoprotein particles have been shown to play critical roles in neuronal membrane homeostasis and synaptic functions (21).”
From APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [21]

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RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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Alzheimer's Disease: cholesterol, membrane rafts, isoprenoids and statins
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Increased Extracellular Amyloid Deposition and Neurodegeneration in Human Amyloid Precursor Protein Transgenic Mice Deficient in Receptor-Associated Protein
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Apolipoprotein E4 is probably responsible for the chromosome 19 linkage peak for Parkinson's disease
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“Although carriers of theAPOE4 gene of apolipoprotein E (apoE) account for more than half of AD patients, the mechanism(s) by which APOE affects the pathogenesis of AD is the subject of continued inquiry (1).”
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APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms
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“In addition, uptake of Aβ through apolipoprotein receptors may be another Aβ clearance pathway (Bu, 2009; Fuentealba et al., 2010; Kanekiyo et al., 2011).”
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In Vivo Introduction of mRNA Encapsulated in Lipid Nanoparticles to Brain Neuronal Cells and Astrocytes via Intracerebroventricular Administration
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Authors: Bu, G.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Bu, Guojun
ORCID: Bu, Guojun
Venue: Nature Reviews Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2009-04-02
Volume: 10
Issue: 5
Pages: 333-344
ISSN: 1471-003X (ISSN-L)
1471-0048
DOI: 10.1038/nrn2620
PMC: PMC2908393
OpenAlex: W2006534012
Cited by: 1,168
References: 156
Citations by year: 2026: 31 · 2025: 49 · 2024: 63 · 2023: 64 · 2022: 58 · 2021: 60 · 2020: 65 · 2019: 74 · 2018: 77 · 2017: 63 · 2016: 84 · 2015: 61 · 2014: 87 · 2013: 85 · 2012: 79
FWCI: 9.07
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Neuroscience (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders: National Institute on Aging (P01AG030128, R01AG027924, R01AG031784)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: apolipoprotein E, APOE ε4, Alzheimer's disease, apoE receptors, amyloid-beta aggregation, amyloid-beta metabolism, cholesterol metabolism, brain lipid metabolism, synaptic function, late-onset Alzheimer's disease, genetic risk factors, Alzheimer's disease treatment
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Humans, Signal Transduction, Low Density Lipoprotein Receptor-Related Protein-1

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Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy

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