Preka, E. | bioRxiv Science

bioRxiv2025

Microglia Adopt Temporally Specific Subtypes after Irradiation, Correlating with Neuronal Asynchrony

Cranial radiotherapy causes progressive neurocognitive impairments in cancer survivors. Neuroinflammation is a key contributor, but its dynamics and consequences for brain function remain poorly understood. Here, we performed comprehensive longitudinal profiling from 6 hours to 1 year after irradiation (IR) of the mouse hippocampus, using transcriptomic, protein, and histological analyses. We identified delayed microglial responses initiated by mitotic progression coupled interferon signaling. IR rewired the parenchymal phagocyte profiles, triggered by progressive microglial loss, failure of repopulation through self-renewal, and compensatory generation of microglia-like cells derived from peripheral monocytes. These findings were also observed in autopsied human brain. Finally, we demonstrate two phases of neuronal asynchrony, an early one associated with inflammation and a late one associated with aberrant synaptic regulation. These results provide comprehensive, longitudinal insights into microglia responses that can aid in tailoring therapies to preserve cognition in cancer survivors.

neuroscience↗

bioRxiv2024

Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression.

Alzheimers disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimers disease onset and progression. Characterizing the initial phase of Alzheimers disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used the AppNL-G-F knock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimers disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis-and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory networks functionality. These results suggest that the early loss of microglia could be a pivotal event in the progression of Alzheimers disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.

neuroscience↗