. Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging. Cell Rep. 2017 Jan 10;18(2):557-570. PubMed.

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  1. This is a very interesting set of data that comes at an opportune time in glial research. Soreq et al. shed further insight into glial heterogeneity among different regions in the human brain, and into how aging affects this heterogeneity across cell types. This study is particularly relevant given the remarkable region-specific vulnerability in neural networks in multiple neurologic diseases, and it highlights the importance of understanding whether and how different glial cells contribute to aging and neurodegeneration.

    We have known for many years now that astrocytes are heterogeneous across and within brain regions (Oberheim et al., 2012). Emerging literature in mouse models suggests that microglia are a diverse population as well; their gene expression is shaped by development, age, resident brain region, sex, and gut microbiota (Hickman et al., 2013; Butovsky et al., 2014; Grabert et al., 2016; Matcovitch-Natan et al., 2016). Recently, Barry McColl’s group (Grabert et al., 2016) beautifully showed that mouse microglia have regionally diverse transcriptomic profiles, and potentially differential sensitivities to aging. The microglia data set from Soreq et al. suggests that whereas there may be less regional heterogeneity in microglia gene expression in human brains, microglial transcriptomic profiles change significantly with aging across brain regions. This is in agreement with both Grabert et al. and Joe El Khoury’s data set in acutely isolated microglia from mice (Hickman et al., 2013), which demonstrated that aging is associated with alterations in immune network, including transcripts encoding for cell surface sensing genes. The important next questions will be to understand how much of these transcriptomic changes translate into functional alterations. What do microglia do in the healthy adult brain, and how do their functions alter with aging? Are microglia responding to specific cues that are changing within their local microenvironment, or are they actively contributing to the aging process? Answering these questions would help us understand their remarkable plasticity in the living brain and gain insight into underlying molecular pathways in aging and disease. Furthermore, it will now be crucial for us to look at the single cell level, while also expanding efforts to understand how the different cell types interact to maintain (or destroy) a functional brain.

    There are already suggestions in the literature for how two of the genes found by Soreq et al. to be upregulated in aging, C1q and Trem2, could be affecting the aging nervous system. Ben Barres’ group showed that the deposition of C1q protein on synapses increases dramatically with aging (Stephan et al., 2013). We have recently shown in mouse models of Aβ-related synaptic pathology that C1q is necessary for oligomeric Aβ to induce synapse loss (Hong et al., 2016). An intriguing question posed is whether with aging, the increase of C1q makes surrounding synapses more vulnerable to loss and dysfunction. While the functions of microglial Trem2 at synapses are still yet to be understood, mutations on Trem2 (or DAP12) lead to progressive presenile dementia in Nasu-Hakola disease (Paloneva et al., 2000, and 2002). Trem2 has also been identified to be a significant risk factor for late-onset Alzheimer’s disease (Guerreiro et al., 2013; Jonsson et al., 2013). Exactly by what mechanisms it affects synaptic pathology still need to be elucidated. However, Soreq et al. provide yet another rationale for focusing on microglia-related pathways in the study of aging and age-related diseases of cognitive decline, including Alzheimer’s. 

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