title: Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis.
abstract: 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.
authors.affiliation: Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.forename: Adam E M
authors.initials: AE
authors.lastname: Eltorai
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Fan
authors.initials: F
authors.lastname: Liao
authors.forename: Philip B
authors.initials: PB
authors.lastname: Verghese
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Kim
authors.forename: Floy R
authors.initials: FR
authors.lastname: Stewart
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Basak
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000276:immunology* / Q000378:metabolism; D001927:Brain Diseases / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D047468:Immunoprecipitation; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018709:Statistics, Nonparametric
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E