Amyloid β peptides alter redox status and oxygen transport function of red blood cells

Abstract Patients with Alzheimer’s disease (AD) exhibit reduced cerebral venous oxygen saturation, that progresses with disease severity and correlates with cognitive decline. The underlying causes of this hypoxia, however, remain unclear. The accumulation of beta-amyloid (Aβ 42 ) and its pathological isoform with isomerized Asp7 (isoAβ 42 ) in the brain are the key pathological factors in AD. Given that red blood cells (RBCs) are the primary carrier of Aβ in the bloodstream and their loading with Aβ 42 increases with age and AD, we studied whether Aβ 42 and isoAβ 42 binding affects human RBC oxygen transport. Here, we demonstrate for the first time that elevated beta-amyloids binding to RBCs reduces hemoglobin oxygen affinity and slows down the rate of oxygen release. This reduction of hemoglobin oxygen affinity is caused by a decrease in the level of reactive oxygen species (ROS). As a result, Aβ 42 binding decreases hemoglobin glutathionylation and its alpha-helical content, whereas isoAβ 42 reduces NO level and alters heme-state of hemoglobin. Importantly, inhibition of NADPH oxidase abolishes the impact of Aβ on ROS, oxygen affinity and alpha-helical content. Therefore, we propose that beta-amyloids impair erythrocyte oxygen affinity primarily through the suppression of NADPH oxidase activity. Moreover, we found a negative correlation between the Aβ 42 amount on the surface of RBCs and the level of intracellular ROS in transgenic APP/PS1-mouse model of AD. The study reveals a new role for Aβ 42 in the regulation of Hb-O₂-affinity and O₂-release from RBCs, raising the possibility of one mechanism underlying the reduced blood oxygen saturation reported in Alzheimer’s disease.