Transcriptomic profiling of microglia and astrocytes throughout aging

Abstract

Background: Activation of microglia and astrocytes, a prominent hallmark of both aging and Alzheimer's disease (AD), has been suggested to contribute to aging and AD progression, but the underlying cellular and molecular mechanisms are largely unknown. Methods:We performed RNA-seq analyses on microglia and astrocytes freshly isolated from wild-type and APP-PS1 (AD) mouse brains at five time points to elucidate their age-related gene-expression profiles.Results: Our results showed that from 4 months onward, a set of age-related genes in microglia and astrocytes exhibited consistent upregulation or downregulation (termed "age-up"/"age-down" genes) relative to their expression at the young-adult stage (2 months). And most age-up genes were more highly expressed in AD mice at the same time points. Bioinformatic analyses revealed that the age-up genes in microglia were associated with the inflammatory response, whereas these genes in astrocytes included widely recognized AD risk genes, genes associated with synaptic transmission or elimination, and peptidase-inhibitor genes.Conclusions: Overall, our RNA-seq data provide a valuable resource for future investigations into the roles of microglia and astrocytes in aging-and amyloid-β-induced AD pathologies.

Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes

“…Other transcriptional factors such as NFAT and STAT3 were also shown to play a role in astrocyte activation, at least in part, via a cross-talk with the NF-κB signaling cascade Cai et al, 2011;Colombo & Farina, 2016;Han et al, 2010;Oeckinghaus, Hayden, & Ghosh, 2011;Sama et al, 2008). This chronic activation of astrocytes may underlie their senescence process, coined "astrosenescence" (Bhat et al, 2012;Cohen & Torres, 2019), which directly impacts neuroinflammation Dresselhaus & Meffert, 2019;Han, Zhang, Liu, Mi, & Gou, 2020;Martinez-Cue & Rueda, 2020;Pan, Ma, Yu, Zhang, & Wan, 2020) and neuronal function (Ceyzeriat et al, 2018;Chinta et al, 2018;Csipo, Lipecz, Ashpole, Balasubramanian, & Tarantini, 2020;Furman et al, 2012;Lattke, Reichel, Magnutzki, et al, 2017;Limbad et al, 2020;Xia, Xie, Ding, Du, & Hu, 2020).…”

Control of microglial dynamics by Arp2/3 and the autism and schizophrenia-associated protein Cyfip1

“…Our data suggest that reduced Cyfip1 and Arp2/3 signalling could contribute to altered morphology during activation. Interestingly, downregulation of Arp complex-related genes has been reported in several contexts where microglia are activated; microglial Cyfip1 levels are reduced in LPS-infused mouse brain, and RNA sequencing from both human and mouse microglia in ageing cortex showed a downregulation of Arp2/3 components ARPC1A and ARPC1B, alongside CYFIP1 and WASF2 (Galatro et al, 2017;Pan et al, 2020;Zhang et al, 2014). Whether altered expression of these genes augments microglial activation in pathological contexts remains to be seen.…”

Astrocytes: News about Brain Health and Diseases

“…At present, the research is clear that the properties of astrocytes, widespread in young age, are also maintained in mature mice and rats if in good health [ 12 , 13 , 14 , 15 ]. During aging, however, many changes and alterations have been reported [ 16 , 17 , 18 , 19 ]. The interactions of heterogeneous astrocytes with neurons are critical for many key events of brain development and function, including the formation and function of synapses, their release and reuptake of transmitters, the production of trophic and toxic factors, and the control of neuronal survival [ 12 , 13 ] ( Figure 1 ).…”

“…The interactions of heterogeneous astrocytes with neurons are critical for many key events of brain development and function, including the formation and function of synapses, their release and reuptake of transmitters, the production of trophic and toxic factors, and the control of neuronal survival [ 12 , 13 ] ( Figure 1 ). These interactions are due to the molecular properties of astrocytes, with differences in the expression of distinct genes (a) at various stages of their functions; (b) at various regions of the brain [ 20 ]; (c) in neuronal circuit regulation [ 21 ], and (d) also in the course of their pathologies [ 16 , 17 , 18 , 19 ].…”

“…The traditional effects of astrocyte aging, induced by their interaction with neurons, vary depending on the state of the latter cells, healthy or sick. Changes are accompanied by forms of neuroinflammation sustained by cytokines, released by astrocytes and microglia [ 19 ]. In many such cases, the astrocyte interactions/communications with neighboring cells are reduced, while their expression of relevant factors, including brain-derived neural factor (BDNF) declines progressively [ 19 , 20 , 23 ].…”