Clinician Scientist-Programm 2026

Thema: "APOE4-dependent immune-vascular dysfunction drives blood-brain barrier breakdown and neuroinflammation in sepsis-associated encephalopathy"

Zusammenfassung:
Sepsis-associated encephalopathy (SAE) is one of the most common complications of severe sepsis worldwide. In the acute stage, SAE is characterized by neuro-psychiatric symptoms such as delirium. After surviving sepsis and in the chronic stage patients continue to show neurocognitive deficits. In previous studies, we have identified long-lasting cognitive deficits in a mouse model of polymicrobial sepsis. We recognized increased phagocytosis of complement-marked synapses by activated microglia as an underlying pathophysiological mechanism during SAE. Building on this, the central premise is that APOE4-driven neurovascular dysfunction represents an upstream event, with neuroinflammation and cognitive decline emerging as downstream consequences. Specifically, we will test the hypotheses that (i) APOE4 aggravates clinical severity and neurocognitive outcomes following SAE, (ii) APOE4 drives neurovascular injury and blood–brain barrier dysfunction as an upstream event, and (iii) targeted reduction of APOE expression using antisense oligonucleotides partially rescues neurovascular integrity, attenuates neuroinflammation, and improves cognitive outcomes. By integrating experimental and translational approaches, this project aims to establish APOE4-driven immune–vascular dysfunction as a mechanistic link between sepsis-associated encephalopathy and neurodegenerative disease pathways.