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

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 bind...

Full description

Saved in:
Bibliographic Details
Published in:Alzheimer's & dementia 2024-02, Vol.20 (2), p.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: Article
Language:English
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1552-5260
1552-5279
1552-5279
DOI:10.1002/alz.13436