title: Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging.
abstract: 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.
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Lilach
authors.initials: L
authors.lastname: Soreq
authors.affiliation: MRC Edinburgh Brain Bank, Academic Neuropathology, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rose
authors.affiliation: The Computational, Cognitive and Clinical NeuroImaging Laboratory, Division of Brain Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Eyal
authors.initials: E
authors.lastname: Soreq
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK; Reta Lila Weston Institute of Neurological Studies, UCL ION, 1 Wakefield Street, London WC1N 1PJ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK; Departments of Genetics, King Faisal Specialist Hospital and Research Centre. Riyadh 12713, Saudi Arabia.
authors.forename: Daniah
authors.initials: D
authors.lastname: Trabzuni
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.affiliation: MRC Edinburgh Brain Bank, Academic Neuropathology, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK; Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Reta Lila Weston Institute of Neurological Studies, UCL ION, 1 Wakefield Street, London WC1N 1PJ, UK; Euan MacDonald Centre for MND, University of Edinburgh, Edinburgh EH8 9YL, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 1TN, UK. Electronic address: rickie.patani@ucl.ac.uk.
authors.forename: Rickie
authors.initials: R
authors.lastname: Patani
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: j.ule@ucl.ac.uk.
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D001921:Brain / Q000378:metabolism*; D002452:Cell Count; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D008875:Middle Aged; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult
keywords: RNA-seq; aging; brain; exon microarrays; gene expression; immunohistochemistry; machine learning; microglia; neurons; olgiodendrocytes