Abstract
BackgroundActivation 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.MethodsWe 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.ResultsOur 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.ConclusionsOverall, 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.
Highlights
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
To clarify the effects of factors associated with late-age disorders of the central nervous system (CNS), we investigated aging-related genes in microglia and astrocytes isolated from the mouse brain at 5 time points
Purification of microglia and astrocytes and RNA-seq profiling To investigate whether microglial and astrocyte genes in mice are altered throughout aging, we performed RNAseq at 5 time points encompassing the mature-adult stage (2 months), when developmental changes in gene expression have ceased, and the middle-age stage (4 months, 6 months, 9 months, 12 months), during which age-dependent pathology develops (Fig. 1a)
Summary
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. Aging and Alzheimer’s disease (AD) produce widespread effects on the central nervous system (CNS) that are characterized by cognitive decline, vulnerability to physical illnesses, elevated oxidative stress, and chronic brain inflammation [1]. These biological and pathological processes are associated with diminished blood-brain barrier (BBB) integrity, which leads to the accumulation in the brain of blood-derived proteins [2, 3] and the infiltration of peripheral cells [4,5,6,7,8,9], and multiple lines of evidence indicate that the innate-immune functions. Astrocytes have to date been documented to play essential roles in neurophysiology, such as in release of gliotransmitters (glucose, ATP, and glutamate), communication with neurons, and modulation of synaptic structure [21]
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