Reactive microglia partially envelop viable neurons in prion diseases

Natallia Makarava; Tarek Safadi; Olga Bocharova; Olga Mychko; Narayan P. Pandit; Kara Molesworth; Simone Baiardi; Li Zhang; Piero Parchi; Ilia V. Baskakov

doi:10.1172/JCI181169

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Makarava, N. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Safadi, T. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Bocharova, O. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Mychko, O. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Pandit, N. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Molesworth, K. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Baiardi, S. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Zhang, L. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Parchi, P. in: JCI | PubMed | Google Scholar |

¹Department of Neurobiology, University of Maryland School of Medicine, Baltimore, United States of America

²University Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

³Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, United States of America

Find articles by Baskakov, I. in: JCI | PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI181169.
Copyright © 2024, Makarava et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 3, 2024 - Version history

Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. The current study demonstrated that in prion disease, microglia effectively phagocytose prions or PrP^Sc during early preclinical stages. However, a critical shift occured in microglial activity during the late preclinical stage, transitioning from PrP^Sc uptake to establishing extensive neuron-microglia body-to-body cell contacts. This change was followed by a rapid accumulation of PrP^Sc in the brain. Microglia that enveloped neurons exhibited hypertrophic, cathepsin D-positive lysosomal compartments. However, most neurons undergoing envelopment were only partially encircled by microglia. Despite up to 40% of cortical neurons being partially enveloped at clinical stages, only a small percentage of envelopment proceeded to full engulfment. Partially enveloped neurons lacked apoptotic markers but showed signs of functional decline. Neuronal envelopment was independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. This phenomenon of partial envelopment was consistently observed 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 envelopment of neurons by reactive microglia in the context of an actual neurodegenerative disease, not a disease model.

Version 1 (October 3, 2024): In-Press Preview

Reactive microglia partially envelop viable neurons in prion diseases

Natallia Makarava,¹ Tarek Safadi,¹ Olga Bocharova,¹ Olga Mychko,¹ Narayan P. Pandit,¹ Kara Molesworth,¹ Simone Baiardi,² Li Zhang,³ Piero Parchi,² and Ilia V. Baskakov¹

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Reactive microglia partially envelop viable neurons in prion diseases

Natallia Makarava,1 Tarek Safadi,1 Olga Bocharova,1 Olga Mychko,1 Narayan P. Pandit,1 Kara Molesworth,1 Simone Baiardi,2 Li Zhang,3 Piero Parchi,2 and Ilia V. Baskakov1

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Natallia Makarava,¹ Tarek Safadi,¹ Olga Bocharova,¹ Olga Mychko,¹ Narayan P. Pandit,¹ Kara Molesworth,¹ Simone Baiardi,² Li Zhang,³ Piero Parchi,² and Ilia V. Baskakov¹