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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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“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]
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“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]
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“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]
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“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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“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
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“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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“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
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“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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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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