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 5

Time course of the envelopment.

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Time course of the envelopment. (A) The clinical onset of the disease in...
(A) The clinical onset of the disease in C57BL/6J mice infected with SSLOW via i.p. established using the EPM test. Mice were subjected to EPM sessions once per week starting from the preclinical stage. After the first training sessions (not shown), mice naturally acquired a strong preference for the closed arms. The clinical onset was defined as a time point, when the time on open arms consistently increased in comparison with the noninfected age-matched control group (shown by arrow). n = 5 for control; n = 14 for SSLOW until 119 dpi; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, by Tukey’s multiple-comparison test. (B) Change in the total number of MAP2+ neurons (upper plot) and the percentage of MAP2+ neurons undergoing envelopment (lower plot) during disease progression. Ctrl1 and Ctrl2 are age-matched controls for 64 dpi and terminal, respectively. Aged 740-day-old mice. Colors represent different brains. Dots represent individual fields of view. Average values for each brain are shown as circles. n = 3–5 animals per time point. Means are marked by black lines. Comparison of means with Ctrl1 was performed by nonparametric Mann-Whitney U test. *P < 0.05; **P < 0.01. (C) Representative images of neuronal envelopment in the cerebral cortex of SSLOW-infected C57BL/6J mice collected at 92 dpi, 106 dpi, 122 dpi (disease onset), and 146 dpi. (D) Representative images of aged brains (740 days old). Staining with anti-IBA1 (red) and anti-MAP2 (green) antibodies. Arrows point at neurons undergoing envelopment. Scale bars: 50 μm.