Microglial brain region-dependent diversity and selective regional sensitivities to ageing

By Kathleen Grabert, Tom Michoel, M. Karavolos, S. Clohisey, J. Baillie, M. Stevens, Tom C. Freeman, K. Summers, B. McColl. Nature Neuroscience, 2016

1,023 citations recorded by the source corpus.

Microglia have critical roles in neural development, homeostasis and neuroinflammation and are increasingly implicated in age-related neurological dysfunction. Neurodegeneration often occurs in disease-specific, spatially restricted patterns, the origins of which are unknown. We performed to our knowledge the first genome-wide analysis of microglia from discrete brain regions across the adult lifespan of the mouse, and found that microglia have distinct region-dependent transcriptional identities and age in a regionally variable manner. In the young adult brain, differences in bioenergetic and immunoregulatory pathways were the major sources of heterogeneity and suggested that cerebellar and hippocampal microglia exist in a more immune-vigilant state. Immune function correlated with regional transcriptional patterns. Augmentation of the distinct cerebellar immunophenotype and a contrasting loss in distinction of the hippocampal phenotype among forebrain regions were key features during aging. Microglial diversity may enable regionally localized homeostatic functions but could also underlie region-specific sensitivities to microglial dysregulation and involvement in age-related neurodegeneration.

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/6b96ab2e0402d6b0d49432966a32e87800008767

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Citations in the corpus

Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017, methodology): “The human transcriptome was compared to this data set as well as to recently published cortical mouse microglial expression data sets 23,24 using the strategy explain above.”
Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response (2018, background): “, Cohen, M., and Schwartz, M. (2013). Microglia and monocyte-derived”
Normal aging induces A1-like astrocyte reactivity (2018, background): “For instance, microglia, the resident immune cells of brain, up-regulate immune response signaling receptors (15), and neuroprotective signaling pathways (16) in aged mice.”
Overview of General and Discriminating Markers of Differential Microglia Phenotypes (2020, background): “…can be detected between microglia expressing CD11b+/CD45low and macrophages expressing CD11b+/CD45high (Ford et al., 1995; Zhang et al., 2002; Grabert et al., 2016), although caution must be taken because CD45 expression increases in microglia upon inflammation and Frontiers in Cellular…”
The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain (2018, result): “Microglia also show alterations in gene expression in the aging brain, and, as with astrocytes, these changes vary by brain region, with cerebellar microglia showing the most changes with age, the same result we found for astrocytes (Grabert et al., 2016).”
The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques (2019, background): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Heterogeneity of microglia between different brain areas (Grabert et al., 2016) and between different sexes (Villa et al., 2018) is increasingly recognized.”
Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes (2018, background): “Microglia may exacerbate some of these deleterious processes by driving or perpetuating brain inflammation through increased expression of inflammatory molecules (Grabert et al., 2016; Hickman et al., 2013).”
Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing (2018, neutral): “…morphologies (Lawson et al., 1990), which seem to correlate with region-specific expression profiles (Ayata et al., 2018; De Biase et al., 2017; Grabert et al., 2016), it remains unclear whether there are molecularly defined subtypes of microglia in the adult brain and, if so, how they are…”
Microglia states and nomenclature: A field at its crossroads (2022, neutral): “68,69,91 Relatively small transcriptional differences may, however, lead to relevant functional differences, as exempliﬁed by the functional variations between hippocampal and cerebellar microglia.”
Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain (2017, background): “398 Cell Reports 18, 391–405, January 10, 2017 revealed GO processes previously identified to be upregulated in microglia (Grabert et al., 2016), including immune response and macromolecule biosynthesis (Figure 6D).”