Paper
- Alzforum Recommends
Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, Tipton T, Chapman MA, Riecken K, Beccari S, Sierra A, Molnár Z, Cragg MS, Garaschuk O, Perry VH, Gomez-Nicola D. Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain. Cell Rep. 2017 Jan 10;18(2):391-405. PubMed.
Recommends
Please login to recommend the paper.
Comments
Children's Hospital
Boston Children's Hospital/Harvard Medical School
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.
References:
Oberheim NA, Goldman SA, Nedergaard M. Heterogeneity of astrocytic form and function. Methods Mol Biol. 2012;814:23-45. PubMed.
Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, El Khoury J. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013 Dec;16(12):1896-905. Epub 2013 Oct 27 PubMed.
Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci. 2014 Jan;17(1):131-43. Epub 2013 Dec 8 PubMed.
Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, Freeman TC, Summers KM, McColl BW. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci. 2016 Mar;19(3):504-16. Epub 2016 Jan 18 PubMed.
Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, Ben-Yehuda H, David E, Zelada González F, Perrin P, Keren-Shaul H, Gury M, Lara-Astaiso D, Thaiss CA, Cohen M, Bahar Halpern K, Baruch K, Deczkowska A, Lorenzo-Vivas E, Itzkovitz S, Elinav E, Sieweke MH, Schwartz M, Amit I. Microglia development follows a stepwise program to regulate brain homeostasis. Science. 2016 Aug 19;353(6301):aad8670. Epub 2016 Jun 23 PubMed.
Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, Kim L, Tsai HH, Huang EJ, Rowitch DH, Berns DS, Tenner AJ, Shamloo M, Barres BA. A Dramatic Increase of C1q Protein in the CNS during Normal Aging. J Neurosci. 2013 Aug 14;33(33):13460-74. PubMed.
Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.
Paloneva J, Kestilä M, Wu J, Salminen A, Böhling T, Ruotsalainen V, Hakola P, Bakker AB, Phillips JH, Pekkarinen P, Lanier LL, Timonen T, Peltonen L. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet. 2000 Jul;25(3):357-61. PubMed.
Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet. 2002 Sep;71(3):656-62. Epub 2002 Jun 21 PubMed.
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):107-16. Epub 2012 Nov 14 PubMed.
View all comments by Soyon HongMake a Comment
To make a comment you must login or register.