Neuropharmacology

Biography

Biography: Sholpan Askarova

Abstract

There is an increasing body of evidence that Blood-Brain Barrier (BBB) dysfunctions contribute significantly to the development and progression of Alzheimer’s Disease (AD). Since Cerebral Endothelial Cells (CECs) are the main cell components of the BBB, we studied the effects of Amyloid β peptide oligomers (Aβ42) on the adhesion mechanisms of cerebral endothelium and role of the Receptor for Advanced Glycation End-Products (RAGE) and Reactive Oxygen Species (ROS) in Aβ mediated cell toxicity and downstream cell signalin pathways in CECs. Increased deposition of amyloid β peptide in cerebral vasculature and enhanced transmigration of monocytes across the BBB are frequently observed in AD brains. Since rolling adhesion is the initial step in the transmigration of monocytes and is governed by dynamic bond formation and rupture between selectins and Sialyl LewisX (sLex), we applied Atomic Force Microscopy (AFM) with cantilever tips bio-functionalized by sLex to examine the effects of Aβ42 on the sLex-selectin adhesion at the surface of CECs and demonstrated that A42 increases the probability of cell adhesion to sLex-coated cantilevers and cell elasticity, and that effects can be counteracted by statin. We also report that Aβ42 promotes expression of P- selectin and increases actin polymerization, and these events are correlated with elevated Reactive Oxygen Species (ROS) production. There is evidence that Aβ mediate oxidative damage to CECs and and trigger the downstream MAPK/ERK pathway. Still, the cell surface binding site for Aβ42 and exact sequence of these events have yet to be elucidated. In this study, the Receptor for Advanced Glycation End-Products (RAGE) was postulated to function as a signal transducing cell surface receptor for Aβ42 to induce Reactive Oxygen Species (ROS) generation from NADPH oxidase and trigger downstream pathways for the phosphorylation of extracellular signal-regulated kinases (ERK1/2) and cytosolic phospholipase A2 (cPLA2). We found that Aβ42 competed with the anti-RAGE antibody (AbRAGE) to bind to RAGE on the surfaces of CECs. In addition, AbRAGE abrogate Aβ42-induced ROS production and the colocalization between the cytosolic (p47-phox) and membrane (gp91-phox) subunits of NADPH oxidase. AbRAGE as well as NADPH oxidase inhibitor and ROS scavenger suppressed Aβ42 -induced ERK1/2 and cPLA2 phosphorylation in CECs. Our findings demonstrating an effect of Aβ42 oligomers on CECs selectin adhesion and the role of Aβ-RAGE interaction in BBB dysfunctions provide insights into the mechanism of inflammation in AD brains and may offer new approaches for prevention and treatment of the disease.