Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice
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BACKGROUND: Human apolipoprotein E (apoE) exists in three major isoforms: apoE2, apoE3 and apoE4. In the brain, apoE is produced mostly by astrocytes and transports cholesterol to neurons via apoE receptors. Among the gene alleles encoding the three isoforms, the APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), whereas APOE2 is protective. ApoE4 confers a gain of toxic function, a loss of neuroprotective function or a combination of both in AD pathogenesis. Given that therapeutic impacts of modulating apoE expression may be isoform-dependent, we sought to investigate the relationship between overexpressing apoE isoform and apoE-related functions in apoE-targeted replacement (TR) mice. Specifically, apoE isoform expression driven by the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter was built into an adeno-associated virus serotype 8 (AAV8) vector and injected into the ventricles of postnatal day 2 (P2) apoE3-TR or apoE4-TR mice. Upon confirmation of apoE isoform expression, effects on apoE lipidation and the levels of amyloid-β (Aβ) in the brain were assessed. RESULTS: AAV8-GFAP-apoE isoforms were specifically expressed in astrocytes throughout all brain regions, which led to overall increased apoE levels in the brain. Viral mediated overexpression of apoE4 in the apoE4-TR background increased poorly-lipidated apoE lipoprotein particles and decreased apoE-associated cholesterol in apoE4-TR mice. Conversely, apoE2 overexpression in apoE4-TR mice enhanced apoE lipidation and associated cholesterol. Furthermore, overexpression of apoE4 elevated the levels of endogenous Aβ, whereas apoE2 overexpression trended to lower endogenous Aβ. CONCLUSIONS: Overexpression of apoE isoforms induces differential effects in the apoE4-TR background: apoE4 decreases apoE lipidation and enhances Aβ accumulation, whereas apoE2 has the opposite effects. Our findings suggest that increasing apoE2 in APOE4 carriers is a beneficial strategy to treat AD, whereas increasing apoE4 in APOE4 carriers is likely harmful. We have also established novel methods to express apoE isoforms in mouse brain to study apoE-related pathways in AD and related dementia.
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In humans, three major isoforms of APOE are lipidated in an isoform-specific manner (ε2 > ε3 > ε4).
“In humans, three major isoforms of APOE are lipidated in an isoform‐specific manner (ε2 > ε3 > ε4). 9 , 48”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [9]
The Results section ('Increasing apoE4 expression leads to decreased apoE lipidation in apoE4-TR mice'; page not provided) says human studies suggest apoE4 is less lipidated than apoE2 and apoE3. It does not establish that apoE2 is more lipidated than apoE3 in humans, so it does not support the full ε2 > ε3 > ε4 ranking. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLipid-poor apoE has greater susceptibility to aggregation, which may impair Aβ clearance and promote Aβ deposition.
“In addition, lipid-poor apoE has been suggested to have greater susceptibility to aggregation, which may impair Aβ clearance and promote Aβ deposition (22).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [22]
The Discussion links possible apoE4 aggregation and poor lipidation to reduced Aβ clearance or increased Aβ deposition. It does not establish that lipid-poor apoE is more susceptible to self-aggregation; it suggests instead that apoE4 aggregation may impair lipidation. The Results discuss lipid-poor apoE promoting Aβ aggregation, which is a different point. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe AAV-GFAP-APOE-HA construct has been previously validated to produce correctly sized, secreted, and lipidated APOE.
“Our AAV-GFAP-APOE-HA construct has been previously validated [10] to produce correctly sized, secreted, and lipidated APOE”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [10]
The Methods section describes AAV8-GFAP constructs encoding HA-tagged apoE, and the Results report apoE expression and apoE-associated lipid particles in transduced mouse brains (pages not provided). The paper does not establish that the expressed apoE protein was correctly sized or directly demonstrate its secretion; the reported molecular sizes refer to apoE-containing particles, not individual apoE proteins. (LLM, conf=0.86)
Experimental — accuracy not yet measuredApoE lipidation is a crucial factor in Alzheimer's disease pathogenesis.
“These small, poorly lipidated apoE particles are similar in size to apoE ε4 particles, further highlighting apoE lipidation as a crucial factor in AD pathogenesis. 8 , 9”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [9]
Small, poorly lipidated apoE particles are similar in size to apoE ε4 particles.
“These small, poorly lipidated apoE particles are similar in size to apoE ε4 particles, further highlighting apoE lipidation as a crucial factor in AD pathogenesis. 8 , 9”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [9]
The aggregation propensity of apoE likely influences its lipidation capacity.
“Imperatively, the aggregation propensity of apoE likely influences its lipidation capacity (22), as dissociation of apoE oligomers to monomers appears to be required for lipid binding to the protein (46).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [22]
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“There was also a significant reduction of A β 42 peptide levels in the hippocampus by 44% (t[9] = 5.983, p = 0.0002, unpaired two-tailed t test; Figure 2B).”
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- Authors
- Hu, J., Liu, C.-C., Chen, X.-F., Zhang, Y.-W., Xu, H., & Bu, G.
- Affiliations
- Xiamen University (CN)
- Mayo Clinic (US)
- Corresponding author
- Bu, Guojun
- Venue
- Molecular Neurodegeneration
- Published
- 2015-03-05
- Volume
- 10
- Issue
- 1
- Pages
- 6-6
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC4356137
- OpenAlex
- W2111723622
- Cited by
- 161
- References
- 51
- Citations by year
- 2026: 7 · 2025: 24 · 2024: 25 · 2023: 13 · 2022: 14 · 2021: 17 · 2020: 16 · 2019: 13 · 2018: 7 · 2017: 12 · 2016: 12 · 2015: 1
- FWCI
- 7.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Alzheimer's Association
- Hope Center for Neurological Disorders
- National Institutes of Health
- National Institute on Aging (P01AG030128, R01AG027924, RF1AG046205, R01AG046205, R01AG035355, P50AG016574)
- National Institute of Neurological Disorders and Stroke (P30NS057105, P01NS074969)
- 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 isoforms, APOE2, APOE ε4, amyloid-beta metabolism, AAV8 vector, glial fibrillary acidic protein promoter, Alzheimer's disease, APOE ε4 carriers
- MeSH terms
- Dependovirus, Alzheimer Disease, Animals, Astrocytes, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Neurons, Amyloid beta-Peptides, Apolipoprotein E4, Apolipoprotein E2
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