Mechanisms of Neuronal Dysfunction and Death in Sepsis-induced Cognitive Impairment

• Applicants: Dr. Julius Emmrich; Professor Dr. Michael Thomas Heneka; Professor Dr. Jonas Neher, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289190824

There is compelling evidence that survivors of critical illness that enter medical care with no evidence of cognitive impairment are often discharged with severe de novo neurocognitive decline that is long-lasting and likely permanent. More than one in three patients have profound cognitive impairments for at least one year after release from an intensive care unit (ICU) and as medical care is improving and the number of ICU admissions is increasing worldwide, the number of survivors of critical illness is growing. Sepsis, a potentially life-threatening systemic inflammation, is a leading cause of ICU admission and commonly precipitates severe long-term cognitive impairment. Recent studies aiming to elucidate the neuronal correlate of cognitive demise have found neuroinflammation (i.e. activation of microglia, the immune cells of the central nervous system, and neuronal death to be responsible for diffuse cerebral damage and eventually brain atrophy. However, the underlying pathophysiology remains poorly understood and there is no available treatment. Microglial phagocytosis (i.e. engulfment and degradation of a target) is a crucial process for the maintenance of brain homeostasis during injury as it prevents tissue damage resulting from leakage of toxic intracellular components from dying cells. Thus, it has previously been assumed that microglial phagocytosis of neurons is entirely beneficial and always preceded by a cell's commitment to cell death. However, based on our recent observations indicating that microglia can engulf and thereby eliminate functional neurons and/or synapses during neuroinflammation, it is conceivable that neuronal and/or synaptic loss following sepsis is executed by microglial phagocytosis. The aim of this proposal is to investigate if phagocytosis of neurons and/or synapses is beneficial or detrimental for cognitive outcome following sepsis. To this end, we will use animal models of endotoxin-induced and polymicrobial cecal ligation and puncture-induced sepsis and will perform detailed biochemical, histological, and behavioural analyses in septic/post-septic phagocytosis-deficient knockout mouse strains. Furthermore, we will directly visualise the changes in neuronal-microglial interaction using in vivo imaging of microglia and neurons. This project will examine the mechanisms of neuronal and/or synaptic loss following sepsis and determine whether anti-phagocytic treatment may be a therapeutic option for preventing cognitive deficits in sepsis survivors.

• DFG Programme: Research Grants