Mark B. De Los Santos

Dysregulated inflammation within the central nervous system (CNS) contributes to neuropathology in infectious, autoimmune, and neurodegenerative disease. With the exception of microglia, major histocompatibility complex (MHC) proteins are virtually undetectable in the mature, healthy central nervous system (CNS). Neurons have generally been considered incapable of antigen presentation, and although interferon gamma (IFN-γ) can elicit neuronal MHC class I (MHC-I) expression and antigen presentation in vitro, it has been unclear whether similar responses occur in vivo. Here we directly injected IFN-γ into the ventral midbrain of mature mice and analyzed gene expression profiles of specific CNS cell types. We found that IFN-γ upregulated MHC-I and associated mRNAs in ventral midbrain microglia, astrocytes, oligodendrocytes, and GABAergic, glutamatergic, and dopaminergic neurons. The core set of IFN-γ-induced genes and their response kinetics were similar in neurons and glia, but with a lower amplitude of expression in neurons. A diverse repertoire of genes was upregulated in glia, particularly microglia, which were the only cells to undergo cellular proliferation and express MHC classII (MHC-II) and associated genes. To determine if neurons respond directly via cell-autonomous IFN-γ receptor (IFNGR) signaling, we produced mutant mice with a deletion of the IFN-γ-binding domain of IFNGR1 in dopaminergic neurons, which resulted in a complete loss of dopaminergic neuronal responses to IFN-γ. Our results demonstrate that IFN-γ induces neuronal IFNGR signaling and upregulation of MHC-I and related genes in vivo, although the expression level is low compared to oligodendrocytes, astrocytes, and microglia.

Progressive cognitive decline in Alzheimer's disease correlates closely with the spread of tau protein aggregation across neural networks of the cortical mantle. We tested the hypothesis that heritable factors may influence the rate of propagation of tau pathology across brain regions in a model system, taking advantage of well-defined genetically diverse background strains in mice. We virally expressed human tau locally in the hippocampus and the entorhinal cortex neurons and monitored the cell-to-cell tau protein spread by immunolabelling. Interestingly, some strains showed more tau spreading than others while tau misfolding accumulated at the same rate in all tested mouse strains. Genetic factors may contribute to tau pathology progression across brain networks, which could help refine mechanisms underlying tau cell-to-cell transfer and accumulation, and potentially provide targets for understanding patient-to-patient variability in the rate of disease progression in Alzheimer's disease.