Targeting of Nonlipidated, Aggregated apoE With Antibodies Inhibits Amyloid Accumulation

J Clin Invest. 2018 May 1;128(5):2144-2155. doi: 10.1172/JCI96429. Epub 2018 Mar 30.

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.

Keywords: Alzheimer’s disease; Neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Antibodies, Monoclonal, Murine-Derived / pharmacology*
  • Apolipoprotein E3 / antagonists & inhibitors
  • Apolipoprotein E3 / genetics
  • Apolipoprotein E3 / metabolism
  • Apolipoprotein E4 / antagonists & inhibitors*
  • Apolipoprotein E4 / genetics
  • Apolipoprotein E4 / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Plaque, Amyloid / drug therapy*
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology

Substances

  • Amyloid beta-Peptides
  • Antibodies, Monoclonal, Murine-Derived
  • Apolipoprotein E3
  • Apolipoprotein E4