APOE Christchurch‐mimetic therapeutic antibody reduces APOE‐mediated toxicity and tau phosphorylation

• Published in: Alzheimer's & dementia Vol. 20; no. 2; pp. 819 - 836
• Main Authors: Marino, Claudia, Perez‐Corredor, Paula, O'Hare, Michael, Heuer, Annie, Chmielewska, Natalia, Gordon, Harper, Chandrahas, Anita S., Gonzalez‐Buendia, Lucia, Delgado‐Tirado, Santiago, Doan, Tri H., Vanderleest, Timothy E., Arevalo‐Alquichire, Said, Obar, Robert A., Ortiz‐Cordero, Carolina, Villegas, Andres, Sepulveda‐Falla, Diego, Kim, Leo A., Lopera, Francisco, Mahley, Robert, Huang, Yadong, Quiroz, Yakeel T., Arboleda‐Velasquez, Joseph F.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2024; John Wiley and Sons Inc
• Subjects: Alzheimer Disease - pathology; Alzheimer's disease; Animals; Antibodies; ApoE; ApoE Christchurch; Apolipoprotein E; Apolipoprotein E3 - genetics; Apolipoprotein E3 - metabolism; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Apolipoproteins E - metabolism; Chromatography; Dementia; drug development; Efficacy; Heparan sulfate; heparan sulfate proteoglycan; Heparan Sulfate Proteoglycans - metabolism; Heparin; HSPG; Humans; Immunologic Factors; Mice; Mutation; Neurodegeneration; Pathology; Phosphorylation; Proteins; Resistance; Sodium; tau phosphorylation; tauopathy; therapeutic antibody; Toxicity; United States > US; heparin; tauopathy; HSPG; Apolipoprotein E; drug development; therapeutic antibody; ApoE; ApoE Christchurch; heparan sulfate proteoglycan; tau phosphorylation; Alzheimer's disease
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.13436

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.