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 Article has an altmetric score of 9

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 10

Microglia engaged in envelopment have activated hypertrophic lysosomes.

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Microglia engaged in envelopment have activated hypertrophic lysosomes. ...
(A) Epifluorescence microscopy images of cortices of noninfected age-matched control and C57BL/6J mice infected with SSLOW via i.p route and examined at the terminal stage using anti–cathepsin D (red) and anti-IBA1 (green) antibodies. (B) Changes in the integrated density of cathepsin D associated with microglia (black) and the percentage of MAP2+ neurons undergoing envelopment (red) with disease progression. Data are represented as mean ± SEM. n = 11–63 fields of view (3–6 brains) per time point. Comparisons to Ctrl (age-matched control for 64 dpi and terminal points) were done using Kruskal-Wallis test followed by Dunn’s multiple-comparisons test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Terminal animals collected at 157–166 dpi. (C and D) 3D reconstruction of confocal microscopy imaging of SSLOW-infected C57BL/6J mice illustrating colocalization of PrPSc (SAF-84, gray) with cathepsin D (red) in microglia (IBA1, green) (C) and envelopment of neurons (NeuN, gray) by cathepsin D–positive (red) microglia (IBA1, green) (D). (E) Maximum intensity projection confocal images of LAMP1+ compartments (green) in microglia (IBA1) in cortices of SSLOW-infected C57BL/6J mice analyzed at the terminal stage along with age-matched control mice. (F) Quantification of LAMP1 integrated density in individual microglial cells engaged or not engaged in neuronal envelopment in cortices of SSLOW-infected mice, and age-matched controls. n = 21–39 individual cells. **P < 0.01; ****P < 0.001, by Kruskal-Wallis test followed by Dunn’s multiple-comparisons test. (G) Confocal microscopy image of LAMP1+ compartments in cortices of SSLOW-infected C57BL/6J mice. Scale bars: 50 μm (A and C); 20 μm (G); 10 μm (D and G).