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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

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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 5

Binding of HAE-1, HAE-4, and control antibody to human apoE4 in the brains of living mice.

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Binding of HAE-1, HAE-4, and control antibody to human apoE4 in the brai...
(A) Control IgG2ab (n = 7), HAE-1 (n = 5), and HAE-4 (n = 6) conjugated with Alexa 594 were applied directly onto the surface of the brain in living APPPS1-21/APOE4 mice that were 6 months of age, and antibody localization was observed using 2-photon microscopy. Amyloid was labeled using methoxy-X04. The signal from Alexa 594 and methoxy-X04 was merged (MERGE) to show the colocalization of antibodies and plaques. (B) Control human IgG (n = 2) or chi–HAE-4 at 50 mg/kg body weight was injected i.p. in 1 dose (0 hour, n = 3) or 2 doses (0 and 48 hour, n = 3). APPPS1-21/APOE4 mice were sacrificed 48 hours after final injection. The antibodies in the brain were detected by biotinylated rabbit anti–human IgG followed by DAB. Left panel, bar = 1 mm. Right panel, high-power image of the indicated areas shown in the left panel; bar = 300 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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