Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Fan Liao, … , Ryan J. Watts, David M. Holtzman
Fan Liao, … , Ryan J. Watts, David M. Holtzman
Published March 30, 2018
Citation Information: J Clin Invest. 2018;128(5):2144-2155. https://doi.org/10.1172/JCI96429.
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Research Article Neuroscience

Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation

Abstract

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.

Authors

Fan Liao, Aimin Li, Monica Xiong, Nga Bien-Ly, Hong Jiang, Yin Zhang, Mary Beth Finn, Rosa Hoyle, Jennifer Keyser, Katheryn B. Lefton, Grace O. Robinson, Javier Remolina Serrano, Adam P. Silverman, Jing L. Guo, Jennifer Getz, Kirk Henne, Cheryl E.G. Leyns, Gilbert Gallardo, Jason D. Ulrich, Patrick M. Sullivan, Eli Paul Lerner, Eloise Hudry, Zachary K. Sweeney, Mark S. Dennis, Bradley T. Hyman, Ryan J. Watts, David M. Holtzman

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Figure 6

Reduction of plaques by HAE-1 and HAE-4 requires effector function.

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Reduction of plaques by HAE-1 and HAE-4 requires effector function. (A) ...
(A) At the age of 4 months, the APPPS1-21/APOE4 mice received 4 i.p. injections of 50 mg/kg of antibodies every 3 days. The mice were sacrificed 24 hours after the final injection and the fibrillar plaques were stained with X-34 and the activated microglia was stained with CD45. The ratio of percentage of area covered by CD45 staining/percentage of area covered by X-34 staining was quantified (equal numbers of male and female mice, n = 8–9/group). (B–E) APPPS1-21/APOE4 mice were injected at day P0 with AAV 2/8 into the lateral ventricle (equal numbers of male and female mice, n = 17–25/group). AAV 2/8 is able to express and secrete full-length HAE-1 and HAE-4 antibodies as well as the same constructs with a D265A mutation in the Fc domain (HAE-1Δ and HAE-4Δ). At the age of 3.5 months, the Aβ plaques (B) were stained with antibody HJ3.4, the fibrillar plaques were stained with X-34 (C), and the insoluble Aβ42 (D) and Aβ40 (E) were measured by ELISA. One-way ANOVA followed by Tukey’s t test was performed to compare different groups shown in A–E. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.