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, apo...

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Bibliographic Details
Published in:The Journal of experimental medicine 2012-11, Vol.209 (12), p.2149-2156
Main Authors: Kim, Jungsu, Eltorai, Adam E M, Jiang, Hong, Liao, Fan, Verghese, Philip B, Kim, Jaekwang, Stewart, Floy R, Basak, Jacob M, Holtzman, David M
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - metabolism
Amyloidosis - immunology
Amyloidosis - metabolism
Amyloidosis - prevention & control
Animals
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal - blood
Antibodies, Monoclonal - pharmacology
Apolipoproteins E - immunology
Apolipoproteins E - metabolism
Brain Diseases - immunology
Brain Diseases - metabolism
Brain Diseases - prevention & control
Brief Definitive Report
Enzyme-Linked Immunosorbent Assay
Immunoblotting
Immunoprecipitation
Immunotherapy - methods
Male
Mice
Mice, Transgenic
Statistics, Nonparametric
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Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20121274