Supportive care or exhausted neglect: the role of microglia at the end stage of prion disease
Victoria A. Lawson
Victoria A. Lawson
Published December 2, 2024
Citation Information: J Clin Invest. 2024;134(23):e186940. https://doi.org/10.1172/JCI186940.
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Commentary

Supportive care or exhausted neglect: the role of microglia at the end stage of prion disease

Abstract

The transmissible nature of prion diseases enables reproduction of neurodegeneration in small animal models that faithfully follows the disease process observed in the natural disease of animals and humans. This allows the temporal development of disease to be investigated and correlated with pathology in a complex brain environment. In this issue of the JCI, Makarava et al. describe a shift in microglia morphology from an active phagocytic phenotype to a passive association with neuronal cell bodies. Whether this morphological change reflects a supportive action of microglia in response to neuronal impairment or exhaustion of PrPSc-laden microglia remains to be determined. However, if microglial populations effectively contain PrPSc propagation early in the infection process, as the current study suggests, identifying ways to maintain or enhance the function of this cell population could be the key to prolonging patient survival.

Authors

Victoria A. Lawson

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Figure 1

Clinical disease in wild-type mice infected with SSLOW prions coincides with microglia that have a neuron-enveloping but not engulfing phenotype.

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Clinical disease in wild-type mice infected with SSLOW prions coincides ...
During the preclinical phase of SSLOW prion infection there is little evidence of neuronal dysfunction or microglial activation. Prions are likely to be propagating and have not reached detectable or clinically relevant levels. Early clinical disease is marked by neuronal dysfunction (indicated by decreased Grin 1 expression) and PrPSc accumulation in microglial cells. Microglial cells later envelop but do not appear to engulf dysfunctional neurons, despite expression of markers of microglial activation and phagocytic activity (indicated by cathepsin D, Gal3, and CD11b). There is a marked increase in the size of the microglial population; however, they do not appear to prevent PrPSc accumulation in the late clinical phase. At the terminal stage of disease, there is a decrease in the neuronal marker Tubb3, suggesting neuronal death. The effects on astrocytes remain unclear.