Protein-associated chemical switches differentially modulate the binding activities of human apolipoprotein E isoforms with their receptors and with amyloid beta peptides.

Abstract

Apolipoprotein E (ApoE) acts as a major cholesterol carrier supporting lipid transport and tissue repair in the brain. The ApoE gene is polymorphic, having three prominent alleles which are the main genetic determinants of Alzheimer Disease (AD) risk in humans. ApoE ε3 has the highest allele frequency in the general population. ApoE ε4 carriers have an increased risk of AD relative to ApoE ε3 carriers, while ApoE ε2 carriers have a decreased risk of developing AD. ApoE proteins bind to several cell surface receptors including low-density lipoprotein receptor (LDLR) and very low-density lipoprotein receptor (VLDLR) to deliver lipids. ApoE binds to Sortilin, which mediates uptake of ApoE containing lipoproteins into neurons, and to amyloid-b (Ab) peptide, which is thought to play important roles in the pathogenesis of AD. We recently discovered that physiological chemicals (such as bicarbonate and sodium hydrogen sulfide) modulate the binding activities of antibodies as a function of the differential external cellular pH between the acidic tumor microenvironment (pH 5.8-6.7 resulting from glycolysis) and the alkaline environment of normal tissues and blood (≥pH7.4). This enables the use of these physiological chemicals as Protein-associated Chemical Switches (PaCS) in cancer therapies1 . Inflamed and senescent cells are glycolytic and are suspected components in the manifestation of AD. We investigated the effects of PaCS molecules on receptor binding as a function of pH. At physiological concentrations, bicarbonate and sodium hydrogen sulfide were observed to differentially affect the binding activities of the ApoE isoforms to LDLR, VLDLR, Sortilin and Aβ peptide. We observed reduced binding of ApoE under alkaline conditions versus acidic conditions, with ApoE ε4 showing the highest binding activity under acidic conditions relative to the other isoforms. Our data indicate that PaCS molecules can conditionally modulate the interactions of different ApoE isoforms with cell surface receptors. These results provide potential mechanistic insights into the differential activity of the ApoE isoforms in normal blood versus acidic tissues associated with inflammation, as well as insights into the potential isoform-dependent protection from PaCS molecules in the pathogenesis of neurodegenerative diseases. Reference: Chang, et al. (2021), PNAS 118(9): 1-10, Suppl 1-19.