Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several statesincluding chemokine-enriched inflammatory microglia-persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human multiple sclerosis lesions. These distinct microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease.

Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical gray versus subcortical white matter, and neurodegeneration at chronic stages. We assessed multilineage cell expression changes using single-nucleus RNA sequencing (snRNA-seq) and validated results using multiplex in situ hybridization in MS lesions. We found selective vulnerability and loss of excitatory CUX2 -expressing projection neurons in upper cortical layers underlying meningeal inflammation; such MS neuron populations showed upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated phagocytosing cells mapped most strongly to the rim of MS plaques. Interestingly, snRNA-seq identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to MS lesion progression.

While the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. Here, we developed a high-content pipeline, the Large-area Spatial Transcriptomic (LaST) map, which can quantify singlecell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, we identified superficial, mid, and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in early postnatal cortex, mostly persisted in adult mouse and human cortex. Single cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.

Aging causes a decline in tissue regeneration due to a loss of function in adult stem and progenitor cell populations 1. An important example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs) 2. A relatively overlooked potential source for this loss of function is the stem cell niche, a source of cell-extrinsic cues including chemical and mechanical signalling 3,4. In this study, we show that the OPC microenvironment stiffens with age, and that this stiffening is sufficient to cause age-related OPC loss of function. Using biological and novel synthetic scaffolds to mimic the stiffness of young brain we find that isolated aged OPCs (aOPCs) cultured on these scaffolds are molecularly and functionally rejuvenated. When we Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Genome-wide association studies (GWAS) have discovered numerous genomic loci associated with Alzheimer’s disease (AD), yet the causal genes and variants remain incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including novel associations near CCDC6 , TSPAN14 , NCK2 , and SPRED2 . Using three SNP-level fine-mapping methods, we identified 21 SNPs with greater than 50% probability each of being causally involved in AD risk, and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci (eQTL) datasets, and prioritization of genes using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we find that evidence converges on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1 , APH1B , PTK2B , PILRA , and CASS4 .

Traumatic brain injury (TBI) is a risk factor for dementia, with studies describing a mixed neurodegenerative pathology in late survivors. However, the mechanisms driving this post-TBI neurodegeneration remain elusive. Increasingly, blood brain barrier (BBB) disruption is recognized in a range of neurological disorders, including dementias; although little is known of the consequences of TBI on the BBB. From the Glasgow TBI Archive autopsy cases of single, moderate or severe TBI (n=70) were selected to include a range of survivals from acute (10h to 13days) to long-term (1 to 47years) survival, together with age-matched, uninjured controls (n=21). Multiple brain regions were examined for fibrinogen (FBG) and immunoglobulin G (IgG) immunohistochemistry. Following TBI, 40% of patients dying in the acute phase and 47% of those surviving a year or more from injury showed multi-focal, abnormal, perivascular and parenchymal FBG and IgG immunostaining localized to grey matter, with preferential distribution towards the crests of gyri and deep neocortical layers. In contrast, where present, controls showed only limited, localized immunostaining. These preliminary data demonstrate evidence of widespread BBB disruption in a proportion of TBI patients emerging in the acute phase and, intriguingly, persisting in a high proportion of late survivors.

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Editorial group: Cochrane Eyes and Vision Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 8, 2015.