Red Blood Cell BPGM Deficiency Contributes to Cognitive Impairment Following Ischemic Stroke - Project Summary/Abstract Cognitive impairment (CI) affects up to 60% of stroke survivors, significantly impacting morbidity and mortality after stroke. Understanding the mechanisms underlying CI following stroke is crucial for early diagnosis and interventions, potentially slowing or preventing the progression of cognitive decline. Our pilot study identified has identified red blood cells (RBCs) as a novel CI risk factor among stroke patients. The levels of the RBC- specific enzyme, bisphosphoglycerate mutase (BPGM), were notably lower in stroke patients with CI compared to those with normal cognitive function. BPGM plays a pivotal role in the glycolytic pathway within RBCs, influencing the production of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-BPG regulates hemoglobin affinity for oxygen to ensure efficient oxygen delivery to tissues. The observed dysregulation of this process may compromise oxygen supply to the brain, exacerbating hypoxic conditions following stroke. In line with this notion, the hypoxia response in brain vascular cells was activated as a result of BPGM deficiency in RBCs. Additionally, RBC BPGM may influence the vascular production of amyloid beta peptides (Aβ) and the integrity of blood brain barrier (BBB). Therefore, we hypothesize that BPGM deficiency within RBCs may contribute to CI in stroke individuals by inducing neurovascular dysfunction. In this R21 research, we aim to delve into the intricate interplay between RBCs, brain vasculature and post stroke cognitive outcome. We will employ a BPGM knockout (KO) mouse model to investigate how BPGM deficiency in RBCs contributes to CI after stroke, and to explore potential therapeutic strategies, with a specific emphasis on the interaction between RBCs and brain vascular system (Aim 1). Subsequently, we will assess the clinical relevance of RBC BPGM- related metabolism by examining its association with post stroke cognitive outcomes in a larger patient cohort (Aim 2). This research uniquely focuses on the overlooked connection between RBCs and vascular dysfunction in the development of CI after stroke, introducing a novel avenue for investigating vascular contributions to cognitive impairment and dementia (VCID). The findings from the study are anticipated to fill a crucial knowledge gap and lay the foundation for innovative therapeutic interventions and potential clinical applications.
