Engulfment of viable neurons by reactive microglia in prion diseases

Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. During brain development, microglia eliminate excessive synapses and neurons, whereas in normal aging and neurodegenerative diseases, microglia are responsible for clearing protein aggregates and cell debris. The current study demonstrates that in prion disease, microglia effectively phagocytose prions or PrP ^Sc during early preclinical stages. However, during the late preclinical stage, a critical shift occurs in microglial activity from PrP ^Sc uptake to the engulfment of neurons. This change occurs before the manifestation of clinical symptoms and is followed by a rapid accumulation of total PrP ^Sc , suggesting a potential link to neuronal dysfunction and behavioral deficits. Surprisingly, the engulfed neurons do not show apoptotic markers, indicating that microglia are targeting viable neurons. Despite up to 40% of neurons being partially engulfed at the clinical stage, there is no significant neuronal loss, suggesting that many engulfment events are incomplete, terminated or protracted. This phenomenon of partial engulfment by reactive microglia is independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. The study establishes partial engulfment as a consistent occurrence across multiple prion-affected brain regions, various mouse-adapted strains, and different subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) in humans. The current work describes a new phenomenon of partial engulfment of neurons by reactive microglia, shedding light on a novel aspect of neuronal-microglia interactions.