Apolipoprotein e sets the stage: response to injury triggers neuropathology
Open accessAbstract
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease and is associated with poor clinical outcome following traumatic brain injury and other neuropathological disorders. Protein instability and an isoform-specific apoE property called domain interaction are responsible for these neuropathological effects. ApoE4 is the most neurotoxic isoform and can induce neuropathology through various cellular pathways. Neuronal damage or stress induces apoE synthesis as part of the repair response; however, when apoE4 is expressed in neurons, its unique conformation makes it susceptible to proteolysis, resulting in the generation of neurotoxic fragments. These fragments cause pathological mitochondrial dysfunction and cytoskeletal alterations. Here, we review data supporting the hypothesis that apoE4 (> apoE3 > apoE2) has direct neurotoxic effects and highlight studies showing that blocking domain interaction reverses these detrimental effects.
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The differences of one or two amino acids among isoforms significantly alter the apoE's folding structure and change its ability to bind lipid and receptor.
“The differences of one or two amino acids among isoforms significantly alter the apoE’s folding structure and change its ability to bind lipid and receptor (Mahley and Huang, 2012).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Mahley and Huang, 2012
The Introduction’s “Structural Differences among the Isoforms” section says single-amino-acid interchanges alter apoE stability and domain interaction, and that the apoE2 substitution causes defective lipoprotein-receptor binding. The copy does not establish that these isoform differences change apoE’s ability to bind lipids; its discussion of lipid capture does not compare isoforms. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNeuron-specific proteolysis of APOE4, resulting in APOE4 fragments in the cytosol, caused toxic effects such as tau phosphorylation, alterations in cytoskeleton, and mitochondrial dysfunctions.
“Neuron-specific proteolysis of APOE4, resulting in APOE4 fragments in the cytosol, caused toxic effects such as tau phosphorylation, alterations in cytoskeleton, and mitochondrial dysfunctions [34,35].”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [35]
The sections on ApoE fragments entering the cytosol and on mitochondrial dysfunction link neuron-generated fragments to cytosolic entry and mitochondrial toxicity. The neurotoxic-effects section reports hyperphosphorylated tau in mice expressing truncated apoE4. However, the cytoskeletal-disruption findings in the neuronal-cytoskeleton section concern apoE4 exposure or expression, not specifically cytosolic apoE4 fragments, so that causal link is not established for every listed effect. (LLM, conf=0.83)
Experimental — accuracy not yet measuredReduced ApoE protein in ApoE4 cells originates from increased proteolytic degradation due to the special conformation of ApoE4.
“reduced ApoE protein in ApoE4 cells was found to originate from increased proteolytic degradation due to the special conformation of ApoE4 (Mahley and Huang, 2012).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Mahley and Huang, 2012
In “ApoE Modulation of the Aβ Pathway” (page unavailable), the paper reports lower apoE4 levels in knock-in mice and describes degradation triggered by apoE4 domain interaction as one explanation. In “Impaired Neuronal Intracellular Trafficking of ApoE” (page unavailable), it says abnormal structure and trafficking likely target apoE4 for proteolysis. These passages support the proposed mechanism, but do not establish that increased proteolytic degradation was found to be the cause of reduced apoE protein across apoE4 cells. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe single amino acid difference increases apoE4 cleavage by a stress-induced neuron-specific protease.
“increases its cleavage by a stress-induced neuron-specific protease [7, 12, 16]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [12]
The ‘ApoE Hypothesis’ section says structural differences make apoE4 more susceptible to neuronal proteolytic cleavage than apoE3 or apoE2. The ‘Neuron-Specific Proteolysis’ section describes the responsible protease as unidentified. The paper says injury or stress induces neuronal apoE synthesis, not that it induces the protease. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe aberrant proteolytic processing of apoE4 and consequent neurotoxicity can be blocked by treating apoE4-expressing cells with small-molecule structure correctors, which convert apoE4 to an apoE3-like conformation and prevent apoE4 fragment generation.
“The aberrant proteolytic processing of apoE4 and consequent neurotoxicity can be blocked by treating apoE4-expressing cells with small-molecule “structure correctors,” which convert apoE4 to an apoE3-like conformation and prevent apoE4 fragment generation [12, 13, 18, 19].”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [12]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
APOE 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 [383]
Neuronal injuries are known to induce apoE expression and such increase in apoE level may help to repair the nervous system by delivering cholesterols and lipids to neurons.
“Neuronal injuries are known to induce apoE expression and such increase in apoE level may help to repair the nervous system by delivering cholesterols and lipids to neurons (Mahley and Huang, 2012).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Mahley and Huang, 2012
The ɛ4 allele has detrimental effects on production, deposition, and clearance of amyloid-β, phosphorylation of tau, neurotoxicity, mitochondrial dysfunction, and blood-brain barrier permeability.
“The ɛ4 allele has detrimental effects on production, deposition, and clearance of amyloid-β, in phosphorylation of tau, in neurotoxicity, mitochondrial dysfunction, and in blood–brain barrier permeability.57,59,60”
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 [12]
ApoE4 increases risk for Alzheimer's disease.
“ApoE4 increases risk for AD”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [12]
Cell-specific toxicity is the result of neuron-specific apoE4 proteolysis.
“Cell-specific toxicity is the result of neuron-specific apoE4 proteolysis [7, 12].”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [12]
The apoE4 domain interaction renders apoE4 more susceptible to proteolytic cleavage, resulting in the generation of neurotoxic apoE4 fragments.
“Importantly, this domain interaction renders apoE4 to be more susceptible to proteolytic cleavage, resulting in the generation of neurotoxic apoE4 fragments [20–22].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [22]
In response to injury or stress such as normal aging, neurons express apoE, likely to facilitate transport of cholesterol and other lipids for membrane repair and/or remodeling.
“In response to injury, or stress such as normal aging, neurons express apoE, likely to facilitate transport of cholesterol and other lipids for membrane repair and/or remodeling [22].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [22]
ApoE plays major roles in Alzheimer's disease pathogenesis in both an amyloid-β-dependent and independent manner.
“Overall, it has been demonstrated, both in vivo and in vitro, that apoE plays major roles in AD pathogenesis in both an Aβ-dependent and independent manner, and different cellular sources of apoE4 may contribute in distinct ways to AD pathogenesis [4–8, 12–14, 21, 22].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [22]
The APOE gene product appears to influence mitochondrial function.
“The APOE gene product, interestingly, also appears to influence mitochondrial function [164-167].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [165]
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References 132 · Cited by 412
- Authors
- Mahley, R. W., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Mahley, Robert W.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 76
- Issue
- 5
- Pages
- 871-885
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4891195
- OpenAlex
- W2064179601
- Cited by
- 412
- References
- 132
- Citations by year
- 2026: 37 · 2025: 37 · 2024: 23 · 2023: 27 · 2022: 35 · 2021: 39 · 2020: 35 · 2019: 28 · 2018: 22 · 2017: 18 · 2016: 29 · 2015: 27 · 2014: 33 · 2013: 21
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (P01 AG022074, R01 AG028793)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- apolipoprotein E, APOE ε4, APOE isoforms, domain interactions, neurotoxicity, traumatic brain injury, Alzheimer's disease, protein instability, proteolysis, mitochondrial dysfunction, cytoskeletal alterations, neuronal stress response, APOE3, APOE2
- MeSH terms
- Animals, Apolipoproteins E, Brain Injuries, Gene Expression Regulation, Humans, Models, Molecular, Nervous System Diseases, Protein Transport
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