Reducing Human Apolipoprotein E Levels Attenuates Age-Dependent Aβ Accumulation in Mutant Human Amyloid Precursor Protein Transgenic Mice
Open accessAbstract
Apolipoprotein E4 (apoE4) plays a major role in the pathogenesis of Alzheimer's disease. Brain amyloid-β (Aβ) accumulation depends on age and apoE isoforms (apoE4 > apoE3) both in humans and in transgenic mouse models. Brain apoE levels are also isoform dependent, but in the opposite direction (apoE4 < apoE3). Thus, one prevailing hypothesis is to increase brain apoE expression to reduce Aβ levels. To test this hypothesis, we generated mutant human amyloid precursor protein transgenic mice expressing one or two copies of the human APOE3 or APOE4 gene that was knocked in and flanked by LoxP sites. We report that reducing apoE3 or apoE4 expression by 50% in 6-month-old mice results in efficient Aβ clearance and does not increase Aβ accumulation. However, 12-month-old mice with one copy of the human APOE gene had significantly reduced Aβ levels and plaque loads compared with mice with two copies, regardless of which human apoE isoform was expressed, suggesting a gene dose-dependent effect of apoE on Aβ accumulation in aged mice. Additionally, 12-month-old mice expressing one or two copies of the human APOE4 gene had significantly higher levels of Aβ accumulation and plaque loads than age-matched mice expressing one or two copies of the human APOE3 gene, suggesting an isoform-dependent effect of apoE on Aβ accumulation in aged mice. Moreover, Cre-mediated APOE4 gene excision in hippocampal astrocytes significantly reduced insoluble Aβ in adult mice. Thus, reducing, rather than increasing, apoE expression is an attractive approach to lowering brain Aβ levels.
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Partial reduction of human APOE level substantially reduced amyloid deposition and neuroinflammation, independent of APOE isoform, implicating overall APOE protein abundance as a key driver of AD pathogenesis.
“Partial reduction of human APOE level substantially reduced amyloid deposition and neuroinflammation, independent of APOE isoform, implicating overall APOE protein abundance itself as a key driver of AD pathogenesis56,57.”
From Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models (2026) · cites this paper as [56]
The Results section, “Halving the levels of apoE significantly attenuates Aβ deposition in aged mice,” reports fewer fibrillar plaques with one rather than two copies of either human APOE3 or APOE4. The Discussion also says the reduction in Aβ accumulation occurred regardless of isoform, while noting that the effects differed by isoform and age. Our copy does not report that reducing APOE lowered neuroinflammation or establish protein abundance as a driver of AD pathogenesis beyond the measured amyloid outcomes in mice. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAlterations in ApoE protein levels and lipidation status strongly influence Aβ metabolism.
“and lipidation status have been shown to strongly influence A metabolism (Kim et al., 2009a,b;Bien-Ly et al., 2012).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Bien-Ly et al., 2012
The Results section, “Halving the levels of apoE significantly attenuates Aβ accumulation in aged mice” (page unavailable), reports that reducing apoE3 or apoE4 levels reduced Aβ accumulation in aged mice. The copy does not establish that apoE lipidation status influences Aβ metabolism; its Discussion mentions other lipid-metabolism processes only as a possible explanation requiring further study. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDeleting one copy of human APOE ε4 or APOE ε3 significantly reduces APOE levels and amyloid pathology in mouse models.
“Other studies have demonstrated that deleting one copy of human APOE ε4 or APOE ε3 significantly reduces APOE levels and amyloid pathology in mouse models.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [6]
The Results section, “Halving the levels of apoE significantly attenuates Aβ accumulation in aged mice” (page unavailable), reports significantly lower Aβ in 12-month-old mice with one rather than two copies of either human apoE3 or apoE4. The Discussion also reports less plaque formation in aged mice, but says 6-month-old mice had similar Aβ levels and deposition with one or two copies. The claim omits this age-dependent qualification. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE3ch did not affect APOE secretion.
“Likewise, APOE3ch did not affect APOE secretion, consistent with prior work demonstrating that APOE stability and secretion are primarily isoform-dependent (E4 < E3 < E2) (Bien-Ly et al., 2012; Wang et al., 2018) and that the Christchurch R136S substitution likely influences receptor-binding and HSPG interactions rather than secretion pathways.”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Bien-Ly et al., 2012
The Introduction (page unavailable) reports lower apoE4 than apoE3 levels and suggests that apoE4 is less stable. The Results (page unavailable) also find lower soluble apoE4 levels in young mice. The paper does not establish an E4 < E3 < E2 ordering for stability or secretion, and it does not study APOE3ch; the APOE3ch secretion result is presented as the citing authors’ own finding, not as this paper’s. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAPP transgenic mice lacking endogenous mouse apoE display a significant decrease of amyloid pathology.
“APP transgenic mice lacking endogenous mouse apoE display a significant decrease of amyloid pathology”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bien-Ly et al 2012
The Results section (page unavailable) reports minimal fibrillar amyloid plaques in hAPP mice lacking apoE, consistent with reduced plaque pathology. But those mice had greater Aβ deposition at 6 months and high Aβ levels and extensive deposition at 12 months. The claim is therefore too broad: the reduction applies to fibrillar plaques, not amyloid pathology generally. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Amyloid deposition in APP transgenic mice occurs in an APOE gene dose-dependent manner, with two copies of human APOE exhibiting more amyloid deposition than one copy.
“amyloid deposition in APP transgenic mice occurs in an APOE gene dose-dependent manner in which mice containing two copies of human APOE gene exhibit more amyloid deposition than those with only one copy”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bien-Ly et al 2012
The Results section (‘Halving the levels of apoE significantly attenuates Aβ deposition in aged mice’) reports more fibrillar amyloid plaques in 12-month-old mice with two human APOE copies than in mice with one, for both APOE3 and APOE4. But the claim omits the age qualification: the Results section on young mice reports no significant difference in Aβ deposition between one and two copies at six months. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLowering APOE levels may confer protection against AD.
“Previous studies suggest that lowering APOE levels may confer protection against AD56–59.”
From Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models (2026) · cites this paper as [56]
Reducing ApoE in mouse models of amyloidosis greatly reduces plaque formation.
“Reducing ApoE in mouse models of amyloidosis greatly reduces plaque formation (7, 8, 33, 34).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [7]
Genetically reducing APOE3 or APOE4 levels decreases amyloid accumulation in APP transgenic mouse models.
“genetically reducing APOE3 or APOE4 levels decreased amyloid accumulation in APP transgenic mouse models [79, 80].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [80]
APOE3 genotype leads to higher total APOE levels compared to APOE4 genotype.
“Research in animal models (Bien-Ly et al., 2012) and hiPSC-based models (Wang et al., 2018) has indicated that the APOE3 genotype leads to higher total APOE levels compared to the APOE4 genotype.”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Bien-Ly et al., 2012
Compaction of protofibrillary Aβ into a dense core plaque requires apoE and is promoted by TREM2.
“the compaction of protofibrillary Aβ into a dense core plaque, which requires apoE and is promoted by TREM2 (Bales et al., 1997b, 1999; Bien-Ly et al., 2012; Wang et al., 2016; Yuan et al., 2016), could be a protective mechanism that limits neurotoxicity of amyloid deposits once they start to build up in the aging brain.”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Bien-Ly et al., 2012
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Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
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Self-citationZalocusky, K. A., Najm, R., Taubes, A. L., Hao, Y., Yoon, S. Y., Koutsodendris, N., Nelson, M. R., Rao, A., Bennett, D. A., Bant, J., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00851-3 · Cited by 189 · see citing works
Self-citationGillespie, A. K., Jones, E. A., Lin, Y.-H., Karlsson, M. P., Kay, K., Yoon, S. Y., Tong, L. M., Nova, P., Carr, J. S., Frank, L. M., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.009 · Cited by 187 · see citing works
Self-citationTargeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Liao, F., Li, A., Xiong, M., Bien-Ly, N., Jiang, H., Zhang, Y., Finn, M. B., Hoyle, R., Keyser, J., Lefton, K. B., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96429 · Cited by 178 · see citing works
Self-citationAnti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
Kim, J., Eltorai, A. E. M., Jiang, H., Liao, F., Verghese, P. B., Kim, J., Stewart, F. R., Basak, J. M., & Holtzman, D. M. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20121274 · Cited by 160 · see citing works
Castellano, J. M., Deane, R., Gottesdiener, A. J., Verghese, P. B., Stewart, F. R., West, T., Paoletti, A. C., Kasper, T. R., DeMattos, R. B., Zlokovic, B. V., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206446109 · Cited by 154 · see citing works
ATP-binding cassette transporter A1: From metabolism to neurodegeneration
Koldamova, R., Fitz, N. F., & Lefterov, I. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.007 · Cited by 144 · see citing works
Kim, J., Yoon, H., Basak, J., & Kim, J. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0248 · Cited by 141 · see citing works
“…several modes of apoE modulation, such as altering its expression level or status of its lipidation, are pursed as promising therapeutic targets (Bien-Ly et al., 2012; Castellano et al., 2011; Cramer et al., 2012; Kim et al., 2009b; 2011; 2012a; 2012b; Liao et al., 2014; Wahrle et al., 2008;).”
BackgroundMahan, T. E., Wang, C., Bao, X., Choudhury, A., Ulrich, J. D., & Holtzman, D. M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00516-0 · Cited by 134 · see citing works
Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits
Koutsodendris, N., Blumenfeld, J., Agrawal, A., Traglia, M., Grone, B., Zilberter, M., Yip, O., Rao, A., Nelson, M. R., Hao, Y., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00368-3 · Cited by 132 · see citing works
Self-citationmicroRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain
Kim, J., Yoon, H., Horie, T., Burchett, J. M., Restivo, J. L., Rotllan, N., Ramírez, C. M., Verghese, P. B., Ihara, M., Hoe, H.-S., et al. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2053-15.2015 · Cited by 128 · see citing works
“We provide a unique approach for AD therapeutics to increase ApoE lipidation and reduce A levels via pharmacological inhibition of microRNA in vivo. and lipidation status have been shown to strongly influence A metabolism (Kim et al., 2009a,b; Bien-Ly et al., 2012).”
BackgroundLiao, F., Hori, Y., Hudry, E., Bauer, A. Q., Jiang, H., Mahan, T. E., Lefton, K. B., Zhang, T. J., Dearborn, J. T., Kim, J., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.0646-14.2014 · Cited by 128 · see citing works
“…between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999; Holtzman et al., 2000; Kim et al., 2011; Bien-Ly et al., 2012) results in decreased amyloidosis.”
BackgroundTong, L. M., Djukic, B., Arnold, C., Gillespie, A. K., Yoon, S. Y., Wang, M. M., Zhang, O., Knoferle, J., Rubenstein, J. L. R., Alvarez-Buylla, A., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.0693-14.2014 · Cited by 123 · see citing works
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Self-citationHan, S.-H., Park, J.-C., & Mook-Jung, I. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.12.004 · Cited by 67 · see citing works
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
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Self-citationProspects for strain-specific immunotherapy in Alzheimer’s disease and tauopathies
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Opposing Roles of apolipoprotein E in aging and neurodegeneration
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MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease
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“However, genetically reducing APOE3 or APOE4 levels decreased amyloid accumulation in APP transgenic mouse models [79, 80].”
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Current insights into apolipoprotein E and the immune response in Alzheimer's disease
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MicroRNAs on the move: microRNAs in astrocyte-derived ApoE particles regulate neuronal function
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APOE loss of function: A genetic shield against Alzheimer’s disease
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Frisch, C., Baker, L., Srinivasan, G., Mintah, A. E., Leyasi, S., Pedroza, M., Galyon, B., & Brafman, D. A. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1856154
- Authors
- Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Huang, Yadong
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-04-04
- Volume
- 32
- Issue
- 14
- Pages
- 4803-4811
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3433173
- OpenAlex
- W2141210743
- Cited by
- 170
- References
- 40
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 12 · 2023: 13 · 2022: 6 · 2021: 7 · 2020: 10 · 2019: 12 · 2018: 10 · 2017: 17 · 2016: 15 · 2015: 11 · 2014: 21 · 2013: 9 · 2012: 11
- FWCI
- 11.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1c06rr018928-01)
- National Institute on Aging (P01AG022074)
- National Institute of Neurological Disorders and Stroke (P30NS065780)
- National Center for Research Resources (C06RR18928, C06-RR-018928)
- 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, APOE ε4, apolipoprotein E3, amyloid-beta deposition, Alzheimer's disease, amyloid precursor protein, amyloid plaques, hippocampal astrocytes, ApoE-deficient mice
- MeSH terms
- Aging, Animals, Apolipoproteins E, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Amyloid beta-Protein Precursor, Mice, Knockout, Mice, Apolipoprotein E3, Apolipoprotein E4, Gene Knock-In Techniques, Mice, 129 Strain
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