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Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFBhi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases. [Display omitted] • Cuprizone-induced de- and remyelination are analyzed by single-nucleus RNA-seq • Oligodendrocytes exhibit a demyelination-specific subset dependent on microglia TREM2 • Astrocytes and vascular cells show metabolic, anti-oxidative, and interferon signatures • Microglia acquire a transcription factor MAFB-induced state during remyelination Hou et al. identify key transcriptional signatures of brain glial and vascular cells during demyelination and remyelination induced by cuprizone using single-nucleus RNA sequencing. They reveal cell-cell interactions that impact these processes and demonstrate that a population of demyelination-associated oligodendrocytes is dependent on a TREM2-mediated microglia response. [ABSTRACT FROM AUTHOR]

The Apolipoprotein E gene (APOE) is of great interest due to its role as a risk factor for late-onset Alzheimer's disease. ApoE is secreted by astrocytes in the central nervous system in high-density lipoprotein (HDL)-like lipoproteins. Structural models of lipidated ApoE of high resolution could aid in a mechanistic understanding of how ApoE functions in health and disease. Using monoclonal Fab and F(ab′) 2 fragments, we characterize the structure of lipidated ApoE on astrocyte-secreted lipoproteins. Our results provide support for the "double-belt" model of ApoE in nascent discoidal HDL-like lipoproteins, where two ApoE proteins wrap around the nanodisc in an antiparallel conformation. We further show that lipidated, recombinant ApoE accurately models astrocyte-secreted ApoE lipoproteins. Cryogenic electron microscopy of recombinant lipidated ApoE further supports ApoE adopting antiparallel dimers in nascent discoidal lipoproteins. • Astrocyte ApoE adopts an antiparallel dimer in discoidal lipoproteins • Recombinant ApoE adopts an antiparallel dimer in discoidal lipoproteins • Lipid composition affects lipoprotein diameter Apolipoprotein E (ApoE) is the largest genetic risk factor for late-onset Alzheimer's disease. Utilizing cryo-EM, Strickland et al. demonstrate important insights into the structure of lipidated ApoE. ApoE was found to adopt an antiparallel dimer in discoidal lipoproteins secreted by astrocytes and in artificially lipidated recombinant ApoE. [ABSTRACT FROM AUTHOR]