Targeting S100B in Cerebral Ischemia and in Alzheimer's Disease

Abstract

S100B is an EF-hand calcium-binding protein that exerts both intracellular and extracellular effects on a variety of cellular processes. The protein is predominantly expressed in the central nervous system by astrocytes, both physiologically and during the course of neurological disease. In the healthy adult brain and during development, constitutive S100B expression acts as a trophic factor to drive neurite extension and to referee neuroplasticity. Yet, when induced during central nervous system disease, the protein can take on maladaptive roles and thereby exacerbate brain pathology. Based on genetic and pharmacological lines of evidence, we consider such deleterious roles of S100B in two common brain pathologies: ischemic stroke and Alzheimer's disease (AD). In rodent models of ischemic brain damage, S100B is induced early on during the subacute phase, where it exacerbates gliosis and delayed infarct expansion and thereby worsens functional recovery. In mouse models of AD, S100B drives brain inflammation and gliosis that accelerate cerebral amyloidosis. Pharmacological inhibition of S100B synthesis mitigates hallmark pathologies of both brain diseases, opening the door for translational approaches to treat these devastating neurological disorders.