Reactive microglia partially envelop viable neurons in prion diseases
Natallia Makarava, … , Piero Parchi, Ilia V. Baskakov
Natallia Makarava, … , Piero Parchi, Ilia V. Baskakov
Published October 3, 2024
Citation Information: J Clin Invest. 2024;134(23):e181169. https://doi.org/10.1172/JCI181169.
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Research Article Infectious disease Neuroscience

Reactive microglia partially envelop viable neurons in prion diseases

Abstract

Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. The current study demonstrates that in prion disease, microglia effectively phagocytose prions or PrPSc during early preclinical stages. However, a critical shift occurred in microglial activity during the late preclinical stage, transitioning from PrPSc uptake to establishing extensive neuron-microglia body-to-body cell contacts. This change was followed by a rapid accumulation of PrPSc 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 phenomenon of partial envelopment of neurons by reactive microglia in the context of an actual neurodegenerative disease, not a disease model.

Authors

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

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Figure 11

Analysis of neuronal envelopment in CD11b–/– mice.

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Analysis of neuronal envelopment in CD11b–/– mice. (A) Incubation time t...
(A) Incubation time to terminal disease in CD11b–/– and C57BL/6J control mice (WT) inoculated with SSLOW via i.c. route. n = 10 animals per group. Mantel-Cox test of survival curves indicated no significant difference between the groups. (B) Densitometric quantification of Western blots for PrPSc, Tubb3, and Gal3 in SSLOW-infected CD11b–/– and WT mice. Data are represented as means ± SD. n = 6–10 per group. *P < 0.05, by 2-tailed, unpaired Student’s t test. (C) Representative Western blots of selected markers in CD11b–/– and WT mice at the terminal stage. For analysis of PrPSc, BHs were digested with PK and stained with 3D17 antibody. (D) Envelopment of neurons by microglia in the cortex of SSLOW-infected CD11b–/– and WT mice at the terminal stage stained using anti-IBA1 (red) and anti-MAP2 (green) antibodies. (E) Percentage of MAP2+ neurons undergoing envelopment, the total number of MAP2+ neurons, and IBA1 immunoreactivity in SSLOW-infected CD11b–/– and WT mice at terminal stages. n = 4 animals per group. Colors represent different brains. Dots represent individual values. Average values for each brain are shown as circles. Means are marked by black lines. Scale bar: 20 μm.