Abstract
The aging brain is associated with significant changes in physiology that alter the tissue microenvironment of the central nervous system (CNS). In the aged CNS, increased demyelination has been associated with astrocyte hypertrophy and aging has been implicated as a basis for these pathological changes. Aging tissues accumulate chronic cellular stress, which can lead to the development of a pro-inflammatory phenotype that can be associated with cellular senescence. Herein, we provide evidence that astrocytes aged in culture develop a spontaneous pro-inflammatory and senescence-like phenotype. We found that extracellular vesicles (EVs) from young astrocyte were sufficient to convey support for oligodendrocyte differentiation while this support was lost by EVs from aged astrocytes. Importantly, the negative influence of culture age on astrocytes, and their cognate EVs, could be countered by treatment with rapamycin. Comparative proteomic analysis of EVs from young and aged astrocytes revealed peptide repertoires unique to each age. Taken together, these findings provide new information on the contribution of EVs as potent mediators by which astrocytes can extert changing influence in either the disease or aged brain.
Highlights
Astrocytes are an abundant and critical cell type for neural development including synapse formation and axon myelination, and ensuring homeostasis of the adult central nervous system (CNS)[1]
In this report we have demonstrated that primary murine astrocytes when cultured long-term, and with low-passage number, develop a distinct phenotype from younger cultures that is represented in the effects of their extracellular vesicles (EVs) on oligodendrocytes
We have determined that the aging of primary murine astrocytes in this setting was amenable to therapeutic intervention as we had shown that rapamycin was effective in suppressing the transcriptional and functional phenotypes of aging-related changes in these cells
Summary
Astrocytes are an abundant and critical cell type for neural development including synapse formation and axon myelination, and ensuring homeostasis of the adult central nervous system (CNS)[1]. Proteomic analyses revealed significant changes to the cargo of EVs from aged astrocytes, which could be suppressed by treatment with rapamycin, a compound known to have senescence suppression properties[31,32,33] Taken together, these data demonstrate a novel paradigm wherein astrocytes aged in vitro develop a senescence-like phenotype that is accompanied by alterations in the effect of EVs on the propensity of astrocytes to support OPC differentiation. These data demonstrate a novel paradigm wherein astrocytes aged in vitro develop a senescence-like phenotype that is accompanied by alterations in the effect of EVs on the propensity of astrocytes to support OPC differentiation These findings have implications for understanding the basis for astrocyte phenotypes with aging and their influences on CNS functions
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