Border-associated macrophages in post-stroke hippocampal neurogenesis and cognition

Objective

Stroke is one of the leading causes of death and disability worldwide. Although advances in acute care have reduced mortality, up to 60% of survivors develop post-stroke cognitive impairment (PSCI), a major contributor to long-term disability. Current treatment options are limited to rehabilitation, and the mechanisms driving PSCI remain poorly understood. Recent evidence suggests that the brain borders actively regulate brain function. Border-associated macrophages (BAMs), the most abundant immune cells at these interfaces, are ideally positioned to influence hippocampal neurogenesis and neuronal activity, two processes essential for memory. Preliminary findings indicate that BAMs support hippocampal function in health, but their role in chronic stroke remains unknown. BAMboost aims to unravel how BAMs regulate hippocampal neurogenesis and neuroactivation during PSCI, and to test whether restoring BAM-to-neuron communication can improve cognition. Combining novel cutting-edge approaches including single-cell and spatial transcriptomics, proteomics, advanced imaging, in vitro neurosphere assays, and in vivo stroke models, BAMboost will (1) define the molecular dialogue between BAMs and hippocampal neurons after stroke, (2) test whether post-stroke BAMs acquire neurotoxic properties by using targeted BAM depletion, and (3) assess the therapeutic potential of BAM-derived trophic ligands, delivered through an innovative transcranial lipid nanoparticle approach, to restore hippocampal neurogenesis and memory. BAMboost will provide the first comprehensive characterisation of BAM-neuron communication in chronic stroke and establish proof-of-concept for immune-based therapies. The project is expected to advance the understanding of PSCI and open new avenues for treating other neurological disorders marked by disrupted neurogenesis and cognition.