APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation.
Alzheimers Dement
; 20(2): 819-836, 2024 Feb.
Article
em En
| MEDLINE
| ID: mdl-37791598
ABSTRACT
INTRODUCTION:
We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs).METHODS:
We developed and characterized the binding, structure, and preclinical efficacy of novel antibodies targeting human ApoE-HSPG interactions.RESULTS:
We found that one of these antibodies, called 7C11, preferentially bound ApoE4, a major risk factor for sporadic AD, and disrupts heparin-ApoE4 interactions. We also determined the crystal structure of a Fab fragment of 7C11 and used computer modeling to predict how it would bind to ApoE. When we tested 7C11 in mouse models, we found that it reduced recombinant ApoE-induced tau pathology in the retina of MAPT*P301S mice and curbed pTau S396 phosphorylation in brains of systemically treated APOE4 knock-in mice. Targeting ApoE-HSPG interactions using 7C11 antibody may be a promising approach to developing new therapies for AD.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Apolipoproteína E4
/
Doença de Alzheimer
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article