Role of microglia in chronic neuroinflammation and long-term consequences aft er stroke

Prof. Dr. Andreas Meisel

• B12

Dr. Shima Safaiyan

• B12

Project Summary

Stroke outcome is frequently impacted by short- and long-term sequelae, particularly stroke-associated pneumonia (SAP) and post-stroke cognitive impairment and dementia (PSCID). Epidemiological data indicate that the risk of PSCID is not only age-dependent but is also significantly increased by SAP. However, the underlying mechanisms that contribute to the delayed occurring PSCID are not yet well understood. Upon stroke, an inflammatory reacti on mediated by activation of microglial cells as well as infiltrating immune cells has been shown to have both beneficial and detrimental effects on stroke outcomes. Microglia are responsible for tissue remodeling and resolution of inflammati on after brain injury to promote recovery and preserve cognitive abilities. While the role of microglia in the acute phase of stroke is well studied, their role in the chronic phase is largely unknown. We hypothesize that the active microglia phenotype in the old brain
as well as the systemic inflammation due to SAP are the key cofactors for microglia dysfunction impairing brain recovery and contributing to PSCID. Consequently, we will investigate the microglial cell responses and their impact on cognition in the chronic phase of stroke in young and old mice (Aim 1). We will identify molecular mechanisms of microgliainduced tissue repair after stroke (Aim 2). We will explore how SAP affects microglial cell function and its effects on cognition (Aim 3). We will use established stroke and SAP models or microglia-depleted mice and perform up to 6-month outcome assessments by behavioral testing and brain imaging. We will use cell culture models, immunohistochemistry, spatial transcriptomics, and proteomics. In a translational approach, we will identify similar microglia signature patterns in human cerebrospinal fluid and postmortem brain samples from stroke patients (Aim 4). A better understanding of the specific contribution of microglia might contribute to the development of a causal treatment of PSCID.