The apolipoprotein E (APOE) 4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid(A) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with A and facilitates A 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-A 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/PS1 E9 mice weekly for 14 wk. HJ6. 3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble A 40 and A 42 levels. Short-term treatment with HJ6. 3 resulted in strong changes in microglial responses around A plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in A 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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