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.
The Botanical Garden of Department of Pharmacognosy, University of Vienna, Austria. Photo by Atanas G. Atanasov.
Lagoon of the seven cities, a twin lake in the crater of a dormant volcano in the western part of the São Miguel island (Azores, Portugal). Photo by Dr. Ana Sanches Silva.
Central Australian desert scene. Photo by Dr. Rohan Davis.
HEK293T cells. Photo by Atanas G. Atanasov.
Tropical rainforest, Queensland, Australia. Photo by Dr. Rohan Davis.
Australian ocean scene. Photo by Dr. Rohan Davis.
Laboratory equipment. Photo by Atanas G. Atanasov.
Rhododendron arboreum flower. Photo by Devesh Tewari.
The Valley of Flowers, Himalaya, India. Photo by Dr. Rajeshwari Singh.
Bryce Canyon, Utah, USA. Photo by Dr. Anupam Bishayee.
Euphorbia prolifera Buch. (Ham) Ex. Photo by Devesh Tewari.
Foothills of Himalaya, India. Photo by Devesh Tewari.
The Valley of Flowers, Himalaya, India. Photo by Dr. Rajeshwari Singh.
Eco-School Festival, Leiria-Portugal, Spring 2018
Polygonum maritimum (L.) (Polygonaceae)- Ourdania beach (Ain Temouchent- west Algeria)- taken by PhD. EL HACI Imad Abdelhamid
Flower blossoms at gardens by the bay Singapore-photo by Dr. Hemanth Kumar Boyina.
