The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Open accessAbstract
The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ and apoE4, and investigated the mechanism underlying these effects. We utilized APPPS1-21 mice crossed to apoE4-knockin mice expressing human apoE4 (APPPS1-21/APOE4). We discovered an anti-human apoE antibody, anti-human apoE 4 (HAE-4), that specifically recognizes human apoE4 and apoE3 and preferentially binds nonlipidated, aggregated apoE over the lipidated apoE found in circulation. HAE-4 also binds to apoE in amyloid plaques in unfixed brain sections and in living APPPS1-21/APOE4 mice. When delivered centrally or by peripheral injection, HAE-4 reduced Aβ deposition in APPPS1-21/APOE4 mice. Using adeno-associated virus to express 2 different full-length anti-apoE antibodies in the brain, we found that HAE antibodies decreased amyloid accumulation, which was dependent on Fcγ receptor function. These data support the hypothesis that a primary mechanism for apoE-mediated plaque formation may be a result of apoE aggregation, as preferentially targeting apoE aggregates with therapeutic antibodies reduces Aβ pathology and may represent a selective approach to treat AD.
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“Several groups have suggested lowering of APOE expression with APOE-antibodies (Gratuze et al, 2022; Liao et al, 2018; Xiong et al, 2021) or using antisense therapy (Huynh et al, 2017) as a therapeutic option for AD.”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Liao et al, 2018
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Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, the apoE found within Aβ plaques is non‐lipidated or poorly lipidated. 60”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Targeting of the non-lipidated version of APOE4 is predicted to be more successful than targeting the lipidated version, as non-lipidated APOE is more likely to co-deposit with Aβ plaques and also to self-associate139”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [139]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“An antibody that preferentially binds to non-lipidated APOE4 has shown promise in reducing Aβ plaques and CAA in a mouse model of β-amyloidosis, as well as decreasing Aβ-driven tau seeding in mice137–139.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [139]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“ApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liao et al 2018
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In the citing paper
“Selective removal of these aggregates by the HAE-4 antibody prevented insoluble amyloid fibril accumulation in APP/PS1-21/ApoE4 mice, without altering total ApoE levels in the brain or plasma (Liao et al., 2018).”
From ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes (2019) · cites this paper as Liao et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The decrease in plaques is likely a result of either improved clearance of Aβ or the fact that poorly or nonlipidated ApoE is associated with greater Aβ seeding and aggregation rather than lipidated ApoE (Fig. 2B) [44].”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [44]
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In the citing paper
“There is always a concern that complete depletion of apoE expression could be harmful for neuronal maintenance, repair, and brain homeostasis”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liao et al 2018
Experimental — accuracy not yet measuredIn the citing paper
“Instead, data suggests the antibody mediates its effect by binding apoE in plaques followed by antibody mediated plaque opsonization by microglia, likely promoting peri-plaque Aβ phagocytosis (Liao et al., 2018).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Liao et al., 2018
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Citations
Cites
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The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease
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Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920
A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline
Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., et al. (2012) · Nature · doi:10.1038/nature11283 · Cited by 1,738
Self-citationThe role of apolipoprotein E in Alzheimer's disease
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Self-citationHuman ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,242 · cited 1×
“However, a large body of literature shows that apoE affects AD at least in part through exacerbating A aggregation and reducing its clearance (7, 20, 21).”
BackgroundSelf-citationNamba, Y., Tomonaga, M., Kawasaki, H., Otomo, E., & Ikeda, K. (1991) · Brain Research · doi:10.1016/0006-8993(91)91092-f · Cited by 1,157
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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
Self-citationThe Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037
Self-citationApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756
Metadata
- Authors
- Liao, F., Li, A., Xiong, M., Bien-Ly, N., Jiang, H., Zhang, Y., Finn, M. B., Hoyle, R., Keyser, J., Lefton, K. B., Robinson, G. O., Serrano, J. R., Silverman, A. P., Guo, J. L., Getz, J., Henne, K., Leyns, C. E. G., Gallardo, G., Ulrich, J. D., Sullivan, P. M., Lerner, E. P., Hudry, E., Sweeney, Z. K., Dennis, M. S., Hyman, B. T., Watts, R. J., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Denali Therapeutics (United States) (US)
- Duke University (US)
- Harvard University (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Liao, Fan
- Li, Aimin
- Xiong, Monica
- Jiang, Hong
- Zhang, Yin
- Finn, Mary Beth
- Hoyle, Rosa
- Lefton, Katheryn B.
- Serrano, Javier Remolina
- Silverman, Adam P.
- Guo, Jing L.
- Getz, Jennifer
- Henne, Kirk
- Leyns, Cheryl E.G.
- Gallardo, Gilbert
- Ulrich, Jason D.
- Sullivan, Patrick M.
- Lerner, Eli Paul
- Sweeney, Zachary K.
- Dennis, Mark S.
- Hyman, Bradley T.
- Watts, Ryan J.
- Holtzman, David M.
- Venue
- Journal of Clinical Investigation
- Published
- 2018-03-30
- Volume
- 128
- Issue
- 5
- Pages
- 2144-2155
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5919821
- OpenAlex
- W2794553092
- Cited by
- 178
- References
- 41
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 24 · 2023: 23 · 2022: 21 · 2021: 15 · 2020: 21 · 2019: 19 · 2018: 14
- FWCI
- 11.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Insitiutes of Health (AG047644)
- Denali (characterization of the effects of apoE antibodies)
- BrightFocus Foundation (Effects of anti-apoE antibodies in APP mice)
- National Institutes of Health (P50 AG05681, P01 AG03991, P01 AG026276)
- 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, APOE ε4, Alzheimer's disease, amyloid-beta, antibody therapy, amyloid plaques, Fc gamma receptor, AAV gene delivery, amyloid accumulation
- MeSH terms
- Alzheimer Disease, Animals, Humans, Amyloid beta-Peptides, Mice, Knockout, Mice, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid, Antibodies, Monoclonal, Murine-Derived
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