Prion diseases are invariably fatal neurodegenerative diseases associated with the accumulation of a misfolded form of the normal cellular prion protein. While the function of the normal cellular form of the prion protein (PrPC) is expansive, the misfolded form of the protein, termed PrPSc, is pathognomonic of prion diseases and synonymous with the transmissible agent, or prion.

As with many other neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, disease-associated protein misfolding can be sporadic, with no defined cause, or familial and associated with mutations in the prion protein gene. However, in prion diseases, the misfolded protein aggregates are also able to transmit the disease through template-directed misfolding of PrPC. Although template-directed misfolding of other neurodegeneration-associated proteins has been described as prion-like, the propagation of PrPSc misfolding can generate infectious prions. Inoculation of small animals with PrPSc, therefore goes beyond modeling a disease that naturally occurs in a wide range of mammals, including humans, but fully reconstitutes it.

Following intracerebral inoculation of wild-type mice with prions, PrPSc can typically be first detected half-way through the incubation period in wild-type mice, with the other hallmarks of prion disease, vacuolation, and glia cell reactivity, specifically astrocytes, appearing shortly thereafter (1). Infectious titers of prions peak within the first third of the incubation period (2), which correlates with the appearance of toxic PrP species that affect neuronal function through changes in long-term potentiation ex vivo (3). However, synaptic loss and clinical signs are typically not observed until the final weeks of the infection period (typically 90% of the incubation period) and correlate with rapid disease progression. Despite this detailed characterization of the pathological and clinical progression of disease, it remains to be determined what precipitates the extraordinarily rapid clinical progression of prion disease.

In this issue of the JCI, Makarava et al. (4) used an intraperitoneal infection with the strain of prions designated as synthetic strain leading to overweight (SSLOW) to investigate the role of microglia in controlling or contributing to the rapid clinical progression that characterizes prion diseases. The authors’ observation of microglia enveloping but not engulfing neurons in late clinical stages of the disease is also observed in the brains of mice infected with ME7, RML, and 22L prion strains and in the brains of patients with Creutzfeldt-Jakob disease (CJD) at terminal disease. This observation attests to the widespread occurrence of this microglia phenotype in prion disease regardless of prion strain type or host species.