38
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Gene expression studies suggest that aging of the human brain is determined by a complex interplay of molecular events, although both its region- and cell-type-specific consequences remain poorly understood. Here, we extensively characterized aging-altered gene expression changes across ten human brain regions from 480 individuals ranging in age from 16 to 106 years. We show that astrocyte- and oligodendrocyte-specific genes, but not neuron-specific genes, shift their regional expression patterns upon aging, particularly in the hippocampus and substantia nigra, while the expression of microglia- and endothelial-specific genes increase in all brain regions. In line with these changes, high-resolution immunohistochemistry demonstrated decreased numbers of oligodendrocytes and of neuronal subpopulations in the aging brain cortex. Finally, glial-specific genes predict age with greater precision than neuron-specific genes, thus highlighting the need for greater mechanistic understanding of neuron-glia interactions in aging and late-life diseases.

          Graphical Abstract

          Highlights

          • Understanding the role of cell-type-specific changes in human brain aging

          • Glial-specific genes shift their regional expression patterns during aging

          • Oligodendrocytes and neuronal subpopulations are decreased in the aging neocortex

          • Microglia-specific genes globally increase their expression during aging

          Abstract

          Human brain aging is determined by a complex interplay of regional and cell-type-specific molecular events. Soreq et al. find that glial genes shift their regional expression patterns, while microglia-specific genes globally increase their expression upon aging. Moreover, immunohistochemistry reveals decreased numbers of oligodendrocytes and neuronal subpopulations in the aging neocortex.

          Related collections

          Most cited references21

          • Record: found
          • Abstract: found
          • Article: not found

          Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function.

          Aging-associated cognitive decline is affected by factors produced inside and outside the brain. By using multiorgan genome-wide analysis of aged mice, we found that the choroid plexus, an interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent gene expression profile that was also found in aged human brains. In aged mice, this response was induced by brain-derived signals, present in the cerebrospinal fluid. Blocking IFN-I signaling within the aged brain partially restored cognitive function and hippocampal neurogenesis and reestablished IFN-II-dependent choroid plexus activity, which is lost in aging. Our data identify a chronic aging-induced IFN-I signature, often associated with antiviral response, at the brain's choroid plexus and demonstrate its negative influence on brain function, thereby suggesting a target for ameliorating cognitive decline in aging. Copyright © 2014, American Association for the Advancement of Science.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Neocortical glial cell numbers in human brains.

            Stereological cell counting was applied to post-mortem neocortices of human brains from 31 normal individuals, age 18-93 years, 18 females (average age 65 years, range 18-93) and 13 males (average age 57 years, range 19-87). The cells were differentiated in astrocytes, oligodendrocytes, microglia and neurons and counting were done in each of the four lobes. The study showed that the different subpopulations of glial cells behave differently as a function of age; the number of oligodendrocytes showed a significant 27% decrease over adult life and a strong correlation to the total number of neurons while the total astrocyte number is constant through life; finally males have a 28% higher number of neocortical glial cells and a 19% higher neocortical neuron number than females. The overall total number of neocortical neurons and glial cells was 49.3 billion in females and 65.2 billion in males, a difference of 24% with a high biological variance. These numbers can serve as reference values in quantitative studies of the human neocortex.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A dramatic increase of C1q protein in the CNS during normal aging.

              The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.
                Bookmark

                Author and article information

                Contributors
                Journal
                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                2211-1247
                10 January 2017
                10 January 2017
                10 January 2017
                : 18
                : 2
                : 557-570
                Affiliations
                [1 ]Institute of Neurology, University College London, London WC1N 3BG, UK
                [2 ]The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
                [3 ]MRC Edinburgh Brain Bank, Academic Neuropathology, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
                [4 ]The Computational, Cognitive and Clinical NeuroImaging Laboratory, Division of Brain Sciences, Imperial College, London SW7 2AZ, UK
                [5 ]Reta Lila Weston Institute of Neurological Studies, UCL ION, 1 Wakefield Street, London WC1N 1PJ, UK
                [6 ]Departments of Genetics, King Faisal Specialist Hospital and Research Centre. Riyadh 12713, Saudi Arabia
                [7 ]Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA
                [8 ]Euan MacDonald Centre for MND, University of Edinburgh, Edinburgh EH8 9YL, UK
                [9 ]Department of Medical and Molecular Genetics, King’s College London, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK
                [10 ]Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 1TN, UK
                Author notes
                []Corresponding author rickie.patani@ 123456ucl.ac.uk
                [∗∗ ]Corresponding author j.ule@ 123456ucl.ac.uk
                [11]

                Lead Contact

                Article
                S2211-1247(16)31684-9
                10.1016/j.celrep.2016.12.011
                5263238
                28076797
                6190db8d-0454-4f4a-a8cf-5cc718956612
                © 2017 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 2 May 2016
                : 4 October 2016
                : 2 December 2016
                Categories
                Resource

                Cell biology
                aging,gene expression,machine learning,immunohistochemistry,brain,neurons,olgiodendrocytes,microglia,exon microarrays,rna-seq

                Comments

                Comment on this article