Abstract:BackgroundAge is the primary risk factor for many diseases. As such, age is a critical co-factor for examination in order to understand the progression and potential intervention in disease progression. Studies examining both the phenotype and transcriptome of aged microglia demonstrated a propensity for the development of a pro-inflammatory phenotype. Less well studied is the concomitant blunting of anti-inflammatory aspects of microglial function with age which also impact plasticity and repair in the CNS.Me… Show more
“…8câf). Recently, a proteomic analysis of isolated microglia from young (3â5Â M) and old (20â24Â M) mice was reported [48]. Comparing the proteins found to be differentially expressed with aging and the transcripts observed here, common induction of Dync1l2, Gltp, Tcirg1, Mobp, Ctsz, Iba1, Ly86, Cyba, and H2-D1 were observed in both studies, with only Fgd2 demonstrating opposite regulation, providing further support that the transcript changes observed here are reflected at the protein level.Fig.…”
BackgroundThe necessity of including both males and females in molecular neuroscience research is now well understood. However, there is relatively limited basic biological data on brain sex differences across the lifespan despite the differences in age-related neurological dysfunction and disease between males and females.MethodsWhole genome gene expression of young (3Â months), adult (12Â months), and old (24Â months) male and female C57BL6 mice hippocampus was analyzed. Subsequent bioinformatic analyses and confirmations of age-related changes and sex differences in hippocampal gene and protein expression were performed.ResultsMales and females demonstrate both common expression changes with aging and marked sex differences in the nature and magnitude of the aging responses. Age-related hippocampal induction of neuroinflammatory gene expression was sexually divergent and enriched for microglia-specific genes such as complement pathway components. Sexually divergent C1q protein expression was confirmed by immunoblotting and immunohistochemistry. Similar patterns of cortical sexually divergent gene expression were also evident. Additionally, inter-animal gene expression variability increased with aging in males, but not females.ConclusionsThese findings demonstrate sexually divergent neuroinflammation with aging that may contribute to sex differences in age-related neurological diseases such as stroke and Alzheimerâs, specifically in the complement system. The increased expression variability in males suggests a loss of fidelity in gene expression regulation with aging. These findings reveal a central role of sex in the transcriptomic response of the hippocampus to aging that warrants further, in depth, investigations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0920-8) contains supplementary material, which is available to authorized users.
“…8câf). Recently, a proteomic analysis of isolated microglia from young (3â5Â M) and old (20â24Â M) mice was reported [48]. Comparing the proteins found to be differentially expressed with aging and the transcripts observed here, common induction of Dync1l2, Gltp, Tcirg1, Mobp, Ctsz, Iba1, Ly86, Cyba, and H2-D1 were observed in both studies, with only Fgd2 demonstrating opposite regulation, providing further support that the transcript changes observed here are reflected at the protein level.Fig.…”
BackgroundThe necessity of including both males and females in molecular neuroscience research is now well understood. However, there is relatively limited basic biological data on brain sex differences across the lifespan despite the differences in age-related neurological dysfunction and disease between males and females.MethodsWhole genome gene expression of young (3Â months), adult (12Â months), and old (24Â months) male and female C57BL6 mice hippocampus was analyzed. Subsequent bioinformatic analyses and confirmations of age-related changes and sex differences in hippocampal gene and protein expression were performed.ResultsMales and females demonstrate both common expression changes with aging and marked sex differences in the nature and magnitude of the aging responses. Age-related hippocampal induction of neuroinflammatory gene expression was sexually divergent and enriched for microglia-specific genes such as complement pathway components. Sexually divergent C1q protein expression was confirmed by immunoblotting and immunohistochemistry. Similar patterns of cortical sexually divergent gene expression were also evident. Additionally, inter-animal gene expression variability increased with aging in males, but not females.ConclusionsThese findings demonstrate sexually divergent neuroinflammation with aging that may contribute to sex differences in age-related neurological diseases such as stroke and Alzheimerâs, specifically in the complement system. The increased expression variability in males suggests a loss of fidelity in gene expression regulation with aging. These findings reveal a central role of sex in the transcriptomic response of the hippocampus to aging that warrants further, in depth, investigations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0920-8) contains supplementary material, which is available to authorized users.
“…Activating microglia is not sufficient to rescue the impaired phagocytic activity of aging microglia. A recent proteomic analysis of aged microglia identified a shift in transcription, bioenergetics and nutrient responses via the mTOR pathway (Flowers et al, 2017). All these parameters induce an increased inflammatory response in the aging brain.…”
Section: Microglial Function In the Ageing Brain 331 | Time Divermentioning
confidence: 99%
“…Alternatively, inflammatory regulatory pathways are impaired with age, which elicits a hyper-activated microglial status. A recent proteomic analysis of aged microglia identified a shift in transcription, bioenergetics and nutrient responses via the mTOR pathway (Flowers et al, 2017). The researchers hypothesized that aged microglia would shift from using glucose as an energy source to oxidizing ketones and fatty acids.…”
Microglia are resident macrophages of the central nervous system; they arise during early embryonic development and persist throughout adulthood. These unique cells provide developmental support, contribute to adult brain homeostasis and impart immune protection during infection. Dysregulated microglia are implicated in the pathophysiology of several neurological disorders, including Alzheimer disease, and as such, a better understanding of their regulation and function is required for rational therapeutic design. Recent studies have highlighted the various heterogeneous aspects of microglia, such as their wide differentiation spectrum from early embryogenesis to adulthood, their location in different brain regions and their responses to ageing, infection and inflammation. In this review, we discuss microglial heterogeneity in time and space and highlight the remaining questions arising from such heterogeneity.
“…It is known, however, that only a relatively small percentage of expressed transcripts will be translated to proteins; thus, future research will also require advancing our understanding of the proteome heterogeneity. Indeed, one such study has examined the proteome of microglia from the brains of young and aged mice but without analyzing the varied profiles from different brain regions (143).…”
Section: Expression Profiles Of Glial Cells Reveal That Regional Specmentioning
Alzheimer's disease is a progressive, incurable neurodegenerative disease targeting specific neuronal populations within the brain while neighboring neurons appear unaffected. The focus for defining mechanisms has therefore been on the pathogenesis in affected neuronal populations and developing intervention strategies to prevent their cell death. However, there is growing recognition of the importance of glial cells in the development of pathology. Determining exactly how glial cells are involved in the disease process and the susceptibility of the aging brain provides unprecedented challenges. The present review examines recent studies attempting to unravel the glial response during the course of disease and how this action may dictate the outcome of neurodegeneration. The importance of regional heterogeneity of glial cells within the CNS during healthy aging and disease is examined to understand how the glial cells may contribute to neuronal susceptibility or resilience during the neurodegenerative process.âAlibhai, J. D., Diack, A. B., Manson, J. C. Unravelling the glial response in the pathogenesis of Alzheimer's disease. 32, 5766â5777 (2018). http://www.fasebj.org
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