Biology subjects

Mychko, O.

Publications and source records attributed to Mychko, O..

3 recordsLinked to original sources

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↗

bioRxiv2023

Region-specific homeostatic identity of astrocytes is essential for defining their reactive phenotypes following pathological insults

The transformation of astrocytes into reactive states constitutes a biological response of the central nervous system under a variety of pathological insults. Astrocytes display diverse homeostatic identities, which are developmentally predetermined and regionally specified. Upon transformation into reactive states associated with neurodegenerative diseases and other neurological disorders, astrocytes acquire diverse reactive phenotypes. However, it is not clear whether their reactive phenotypes are dictated by regionspecific homeostatic identity or, alternatively, by the nature of an insult. To address this question, regionspecific gene expression profiling was performed for four brain regions (cortex, hippocampus, thalamus and hypothalamus) in mice using a custom Nanostring panel consisting of selected sets of genes that report on astrocyte functions and their reactivity for five conditions: prion disease, traumatic brain injury, brain ischemia, 5XFAD Alzheimers disease model and normal aging. Upon transformation into reactive states, genes that are associated predominantly with astrocytes were found to preserve region-specific signatures suggesting that they respond to insults in a region-specific manner. A common gene set was found to be involved in astrocyte remodeling across insults and normal aging. Regardless of the nature of an insult or insult-specificity of astrocyte response, strong correlations between the degree of astrocyte reactivity and perturbations in their homeostasis-associated genes were observed within each individual brain region. The insult-specific populations did not separate well from each other and instead partially overlapped, forming continuums of phenotypes. The current study demonstrates that astrocytes acquire their reactive phenotypes according to their region-specific homeostatic identities. Within these region-specified identities, reactive phenotypes show continuums of states, partially overlapping between individual insults.

neuroscience↗