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
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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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 9

Time course of PrPSc uptake, neuronal envelopment, and microglia proliferation.

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Time course of PrPSc uptake, neuronal envelopment, and microglia prolife...
Changes in the percentage of PrPSc+ microglia (A), the percentage of MAP2+ neurons under envelopment (B), the total number of IBA1+ microglial cells per field of view (C), the amounts of total PrP (no PK treatment) and PrPSc (after PK treatment) as estimated by Western blot (D), and the total number of PrPSc+ microglia per field of view (E) in C57BL/6J mice infected with SSLOW via i.p. route with disease progression. Data are represented as mean ± SEM. Comparisons with Ctrl (combined age-matched controls 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. n = 18–63 fields of view (3–5 brains) per time point for B, and n = 17–60 (4–5 brains) for A, C, and E. Term, terminal animals collected at 157–166 dpi. Dashed line shows clinical onset. (F) Representative Western blots of total PrP (no PK treatment, -PK), PrPSc (after PK treatment, +PK), Tubb3, CD11b, and Gal3 in brains of SSLOW-infected C57BL/6J mice. PrP is detected by 3D17 antibody. (G) Quantification of Western blots of Tubb3, CD11b, and Gal3; signal intensities were normalized per intensities of actin for each individual Western blot. In F and G, Ctrl1 and Ctrl2 are age-matched controls for 64 dpi and terminal time points, respectively. Data are represented as means ± SD. n = 3–5 animals per group, *P < 0.05; ***P < 0.001; **** P < 0.0001; each time point was compared with the combined control group (Ctrl1 + Ctrl2) by Brown-Forsythe and Welch’s ANOVA followed by Dunnett’s T3 multiple-comparison tests.