A transcriptomic atlas of aged human microglia

Olah, Marta; Patrick, Ellis; Villani, Alexandra‐Chloé; Xu, Jishu; White, Charles C.; Ryan, Katie J.; Piehowski, Paul; Kapasi, Alifiya; Nejad, Parham; Cimpean, Maria; Connor, Sarah M.; Yung, Christina J.; Frangieh, Michael; McHenry, Allison; Elyaman, Wassim; Petyuk, Vlad; Schneider, Julie A.; Bennett, David A.; Jager, Philip L. De; Bradshaw, Elizabeth M.

doi:10.1038/s41467-018-02926-5

Cited by 400 publications

(481 citation statements)

References 32 publications

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“…Recent transcriptomic studies, the majority of which have been conducted in mice, have greatly advanced our knowledge of the functional profile of microglia (Butovsky et al, ; Darmanis et al, ; Galatro et al, ; Hickman et al, ; Zeisel et al, ), their regional heterogeneity in the CNS (Grabert et al, ; McCarthy, ), and altered functional profile associated with neurodegeneration (Holtman et al, ; Keren‐Shaul et al, ; Miller et al, ; Vincenti et al, ). However, key differences between mouse and human microglia have been suggested (Galatro et al, ; Olah et al, ), emphasizing the importance of better characterizing the functional profile of human microglia in health and disease. Our initial investigations demonstrated that published microglia gene signatures vary considerably in their size and composition relative to one another.…”

Section: Discussionmentioning

confidence: 99%

A core transcriptional signature of human microglia: Derivation and utility in describing region‐dependent alterations associated with Alzheimer's disease

Patir

Shih

McColl

et al. 2019

Glia

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Growing recognition of the pivotal role microglia play in neurodegenerative and neuroinflammatory disorders has accentuated the need to characterize their function in health and disease. Studies in mouse have applied transcriptome‐wide profiling of microglia to reveal key features of microglial ontogeny, functional profile, and phenotypic diversity. While similar, human microglia exhibit clear differences to their mouse counterparts, underlining the need to develop a better understanding of the human microglial profile. On examining published microglia gene signatures, limited consistency was observed between studies. Hence, we sought to derive a core microglia signature of the human central nervous system (CNS), through a comprehensive analysis of existing transcriptomic datasets. Nine datasets derived from cells and tissues, isolated from various regions of the CNS across numerous donors, were subjected independently to an unbiased correlation network analysis. From each dataset, a list of coexpressing genes corresponding to microglia was identified, with 249 genes highly conserved between them. This core signature included known microglial markers, and compared with other signatures provides a gene set specific to microglia in the context of the CNS. The utility of this signature was demonstrated by its use in detecting qualitative and quantitative region‐specific alterations in aging and Alzheimer's disease. These analyses highlighted the reactive response of microglia in vulnerable brain regions such as the entorhinal cortex and hippocampus, additionally implicating pathways associated with disease progression. We believe this resource and the analyses described here, will support further investigations to the contribution of human microglia in CNS health and disease.

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Section: Discussionmentioning

confidence: 99%

A core transcriptional signature of human microglia: Derivation and utility in describing region‐dependent alterations associated with Alzheimer's disease

Patir

Shih

McColl

et al. 2019

Glia

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“…This shared functionality included microglia as the main cell type, extracellular matrix as the main cellular component, and immune response as the main biological process. Microglia, constituting 5%-12% of all cells in the mouse and human brain (Lawson et al 1990;Lyck et al 2009;Olah et al 2018) and primarily known for their role in immune response, have recently been implicated in multiple brain functions including the regulation of learning-related synapse formation, synaptic plasticity, and cognition (Parkhurst et al 2013;Hong et al 2016;Tay et al 2017) and are linked with neurodegenerative and psychiatric disorders (Wolf et al 2017). Furthermore, microglial cells were shown to have different transcriptional identities in different brain regions (Grabert et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Human-specific features of spatial gene expression and regulation in eight brain regions

Efimova

et al. 2018

Genome Res.

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Molecular maps of the human brain alone do not inform us of the features unique to humans. Yet, the identification of these features is important for understanding both the evolution and nature of human cognition. Here, we approached this question by analyzing gene expression and H3K27ac chromatin modification data collected in eight brain regions of humans, chimpanzees, gorillas, a gibbon, and macaques. An analysis of spatial transcriptome trajectories across eight brain regions in four primate species revealed 1851 genes showing human-specific transcriptome differences in one or multiple brain regions, in contrast to 240 chimpanzee-specific differences. More than half of these human-specific differences represented elevated expression of genes enriched in neuronal and astrocytic markers in the human hippocampus, whereas the rest were enriched in microglial markers and displayed human-specific expression in several frontal cortical regions and the cerebellum. An analysis of the predicted regulatory interactions driving these differences revealed the role of transcription factors in species-specific transcriptome changes, and epigenetic modifications were linked to spatial expression differences conserved across species.

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“…The genomic signature of aged microglia has been of great interest since the advent of next generation sequencing technologies. Unfortunately attempts to characterise them have yielded varied and often conflicting results with no clear and consistent specific genetic or protein markers for aged microglia emerging (Crotti and Ransohoff ; Wes et al ; Spittau ; Olah et al ). The aged microglia in the mouse retina exhibited significant changes in genes controlling inflammation including the NF‐κB signalling pathway and up‐regulated complement genes C3 and complement factor B (Ma et al ).…”

Section: Dystrophic and Senescent Microgliamentioning

confidence: 99%

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

Angelova

Brown

2019

Journal of Neurochemistry

195

125

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The single largest risk factor for etiology of neurodegenerative diseases like Alzheimer’s disease is increased age. Therefore, understanding the changes that occur as a result of aging is central to any possible prevention or cure for such conditions. Microglia, the resident brain glial population most associated with both protection of neurons in health and their destruction is disease, could be a significant player in age related changes. Microglia can adopt an aberrant phenotype sometimes referred to either as dystrophic or senescent. While aged microglia have been frequently identified in neurodegenerative diseases such as Alzheimer’s disease, there is no conclusive evidence that proves a causal role. This has been hampered by a lack of models of aged microglia. We have recently generated a model of senescent microglia based on the observation that all dystrophic microglia show iron overload. Iron‐overloading cultured microglia causes them to take on a senescent phenotype and can cause changes in models of neurodegeneration similar to those observed in patients. This review considers how this model could be used to determine the role of senescent microglia in neurodegenerative diseases.

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A transcriptomic atlas of aged human microglia

Cited by 400 publications

References 32 publications

A core transcriptional signature of human microglia: Derivation and utility in describing region‐dependent alterations associated with Alzheimer's disease

A core transcriptional signature of human microglia: Derivation and utility in describing region‐dependent alterations associated with Alzheimer's disease

Human-specific features of spatial gene expression and regulation in eight brain regions

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

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