Biology subjects

Safadi, T.

Publications and source records attributed to Safadi, T..

3 recordsLinked to original sources

bioRxiv2025

Dissecting surveying behavior of reactive microglia under chronic neurodegeneration

In the healthy brain, microglia maintain homeostasis by continuously surveying neuronal health through highly dynamic processes that form purinergic junctions with neuronal somas. These mechanisms are finely tuned for the rapid detection of acute injuries. However, during the transition to a chronically reactive state in neurodegenerative diseases, microglial ramification decreases even as the need for neuronal monitoring escalates. How reactive microglia adapt their surveillance strategies under these conditions remains poorly understood. Using time-lapse imaging of acute brain slices from prion-infected mice, we identified a previously unrecognized mode of neuronal surveillance employed by reactive microglia. Unlike homeostatic microglia, which exhibit low somatic mobility and high process motility, enabling broad, simultaneous monitoring, reactive microglia display high somatic mobility. These cells actively migrate through the brain parenchyma, pausing to form direct and extensive body-to-body contacts with individual neurons. Contact durations ranged from minutes to several hours, often involving partial or full somatic envelopment, with transitions between these states being both frequent and reversible. Notably, reactive microglia exhibited sustained intracellular calcium bursts correlated with their increased mobility. Pharmacological inhibition of the P2Y6 receptor partially reduced microglial migration without disrupting their ability to form neuronal contacts. Furthermore, this highly mobile behavior persisted in acutely isolated reactive microglia in vitro, even in the absence of external stimuli, indicating that dynamic mobility is an intrinsic feature of the reactive phenotype. These findings reveal a fundamental shift in microglial surveillance architecture during chronic neurodegeneration - transforming from static, multi-neuron monitoring to dynamic, neuron-by-neuron engagement. This work uncovers a novel, adaptive strategy of microglial behavior with critical implications for understanding microglia-neuron interaction under chronic neurodegeneration.

neuroscience↗

bioRxiv2025

Knockout of P2Y12 receptor facilitates microglia-neuron body-to-body interactions and accelerates prion disease

Microglia continuously monitor neuronal health through somatic purinergic junctions, where microglial processes establish dynamic contacts with neuronal cell bodies. The P2Y12 receptor is a key component of these junctions, essential for intercellular communication between ramified microglia and neurons under homeostatic conditions. While P2Y12 has long been considered a marker of homeostatic microglia, its potential role in reactive microglia during neurodegenerative disease remains largely unexplored. In this study, we demonstrate that P2Y12 deletion significantly reduces microglia-neuron process-to-body contacts in adult mice, consistent with previous findings. However, unexpectedly, P2Y12 loss markedly increases microglia-neuron body-to-body contacts, revealing an alternative mode of microglia-neuron communication independent of P2Y12. In prion-infected mice, P2Y12 expression persists in reactive, amoeboid microglia during advanced disease stages, including those engaging in extensive neuronal envelopment. Notably, P2Y12 loss increases the prevalence of envelopment events and accelerates disease progression. These findings redefine the role of P2Y12 in neurodegeneration, suggesting that its progressive decline lowers the threshold for microglia-neuron body-to-body interactions, ultimately influencing disease trajectory.

neuroscience↗

bioRxiv2024

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 PrPSc during early preclinical stages. However, during the late preclinical stage, a critical shift occurs in microglial activity from PrPSc uptake to the engulfment of neurons. This change occurs before the manifestation of clinical symptoms and is followed by a rapid accumulation of total PrPSc, 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.

neuroscience↗