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Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is...

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Autores principales: Kim, Jungsu, Eltorai, Adam E.M., Jiang, Hong, Liao, Fan, Verghese, Philip B., Kim, Jaekwang, Stewart, Floy R., Basak, Jacob M., Holtzman, David M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501350/
https://www.ncbi.nlm.nih.gov/pubmed/23129750
http://dx.doi.org/10.1084/jem.20121274
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author Kim, Jungsu
Eltorai, Adam E.M.
Jiang, Hong
Liao, Fan
Verghese, Philip B.
Kim, Jaekwang
Stewart, Floy R.
Basak, Jacob M.
Holtzman, David M.
author_facet Kim, Jungsu
Eltorai, Adam E.M.
Jiang, Hong
Liao, Fan
Verghese, Philip B.
Kim, Jaekwang
Stewart, Floy R.
Basak, Jacob M.
Holtzman, David M.
author_sort Kim, Jungsu
collection PubMed
description The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
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spelling pubmed-35013502013-05-19 Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis Kim, Jungsu Eltorai, Adam E.M. Jiang, Hong Liao, Fan Verghese, Philip B. Kim, Jaekwang Stewart, Floy R. Basak, Jacob M. Holtzman, David M. J Exp Med Brief Definitive Report The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases. The Rockefeller University Press 2012-11-19 /pmc/articles/PMC3501350/ /pubmed/23129750 http://dx.doi.org/10.1084/jem.20121274 Text en © 2012 Kim et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Kim, Jungsu
Eltorai, Adam E.M.
Jiang, Hong
Liao, Fan
Verghese, Philip B.
Kim, Jaekwang
Stewart, Floy R.
Basak, Jacob M.
Holtzman, David M.
Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
title Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
title_full Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
title_fullStr Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
title_full_unstemmed Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
title_short Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
title_sort anti-apoe immunotherapy inhibits amyloid accumulation in a transgenic mouse model of aβ amyloidosis
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501350/
https://www.ncbi.nlm.nih.gov/pubmed/23129750
http://dx.doi.org/10.1084/jem.20121274
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