Katie Park

The impact of Stress and Amyloidosis on Microglial Phenotypes

Abstract

Microglia are the primary immune cells in the brain (Colonna & Butovsky, 2017). These dynamic cells are heterogeneous in health and disease, with diverse morphology, transcriptional signature, and function. In neurodegenerative conditions like Alzheimer’s disease (AD), microglia assume disease-associated phenotypes that can have protective and harmful functions on the brain (Song & Colonna, 2018). These neurodegenerative properties have been attributed to “dark microglia,” a subset manifesting hallmarks of cellular stress. The integrated stress response (ISR), a conserved stress signaling pathway characterizing the dark microglia subset, has recently been discovered (Flury et al., 2024). In this study, ultrastructural analysis, mean intensity scores of microglial cell bodies, and the proximity of microglia to AD hallmarks were used to determine whether ISR regulates the dark phenotype. The AD pathology model, 5xFAD, possessed the greatest fraction of dark microglia at 0.25 (coronal) and 0.43 (sagittal) suggesting amyloidosis was crucial in dark microglia presence. The majority of microglia in the mouse model of microglia-specific ISR activation was intermediate, demonstrating ISR was insufficient in fully establishing the dark phenotype. Activated ISR in the 5xFAD model intensified the dark phenotype in relation to plaques and the intermediate phenotype near neurites. Typical microglia were absent near all imaged hallmarks. Dark microglia had more than double the mitochondria of typical microglia in 5xFAD models. Lysosomes in typical cells were comparatively nonexistent, suggesting the dark phenotype’s inclination to contain more indigestible components. These findings confirmed that ISR exacerbates the dark phenotype and further found ISR impacts the intermediate phenotype.