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      Normal aging induces A1-like astrocyte reactivity

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          Significance

          In aging, the brain becomes vulnerable to injury and cognitive function declines, but the mechanisms responsible are unknown. Astrocytes, the most abundant class of glial cells, are vital for the proper function of the central nervous system, and impairment of astrocyte function has been implicated in disease. Here we perform RNA sequencing of astrocytes from different brain regions across the lifespan of the mouse to identify age-related transcriptional changes that could contribute to cognitive decline. We find that aged astrocytes take on a reactive phenotype characteristic of neuroinflammatory reactive astrocytes, and that microglia play a role in inducing astrocyte activation. The aging astrocyte RNA sequencing profiles provide an important new resource for future studies exploring the role of astrocytes in cognitive decline.

          Abstract

          The decline of cognitive function occurs with aging, but the mechanisms responsible are unknown. Astrocytes instruct the formation, maturation, and elimination of synapses, and impairment of these functions has been implicated in many diseases. These findings raise the question of whether astrocyte dysfunction could contribute to cognitive decline in aging. We used the Bac-Trap method to perform RNA sequencing of astrocytes from different brain regions across the lifespan of the mouse. We found that astrocytes have region-specific transcriptional identities that change with age in a region-dependent manner. We validated our findings using fluorescence in situ hybridization and quantitative PCR. Detailed analysis of the differentially expressed genes in aging revealed that aged astrocytes take on a reactive phenotype of neuroinflammatory A1-like reactive astrocytes. Hippocampal and striatal astrocytes up-regulated a greater number of reactive astrocyte genes compared with cortical astrocytes. Moreover, aged brains formed many more A1 reactive astrocytes in response to the neuroinflammation inducer lipopolysaccharide. We found that the aging-induced up-regulation of reactive astrocyte genes was significantly reduced in mice lacking the microglial-secreted cytokines (IL-1α, TNF, and C1q) known to induce A1 reactive astrocyte formation, indicating that microglia promote astrocyte activation in aging. Since A1 reactive astrocytes lose the ability to carry out their normal functions, produce complement components, and release a toxic factor which kills neurons and oligodendrocytes, the aging-induced up-regulation of reactive genes by astrocytes could contribute to the cognitive decline in vulnerable brain regions in normal aging and contribute to the greater vulnerability of the aged brain to injury.

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          Most cited references25

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          featureCounts: An efficient general-purpose program for assigning sequence reads to genomic features

          , , (2013)
          Next-generation sequencing technologies generate millions of short sequence reads, which are usually aligned to a reference genome. In many applications, the key information required for downstream analysis is the number of reads mapping to each genomic feature, for example to each exon or each gene. The process of counting reads is called read summarization. Read summarization is required for a great variety of genomic analyses but has so far received relatively little attention in the literature. We present featureCounts, a read summarization program suitable for counting reads generated from either RNA or genomic DNA sequencing experiments. featureCounts implements highly efficient chromosome hashing and feature blocking techniques. It is considerably faster than existing methods (by an order of magnitude for gene-level summarization) and requires far less computer memory. It works with either single or paired-end reads and provides a wide range of options appropriate for different sequencing applications. featureCounts is available under GNU General Public License as part of the Subread (http://subread.sourceforge.net) or Rsubread (http://www.bioconductor.org) software packages.
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            The Microglial Sensome Revealed by Direct RNA Sequencing

            Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.
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              ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

              APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                20 February 2018
                7 February 2018
                7 February 2018
                : 115
                : 8
                : E1896-E1905
                Affiliations
                [1] aDepartment of Neurobiology, Stanford University , School of Medicine, Stanford, CA 94305;
                [2] bNeuroscience Institute, NYU Langone Medical Center , New York, NY 10016;
                [3] cDepartment of Neuroscience and Physiology, NYU Langone Medical Center , New York, NY 10016;
                [4] dBroad Institute of MIT and Harvard , Cambridge, MA 02142;
                [5] ePicower Institute for Learning and Memory , Cambridge, MA 02139;
                [6] fDepartment of Brain and Cognitive Sciences, Massachusetts Institute of Technology , Cambridge, MA 02139
                Author notes
                1To whom correspondence should be addressed. Email: lclarke2@ 123456stanford.edu .

                Edited by Carla J. Shatz, Stanford University, Stanford, CA, and approved January 19, 2018 (received for review December 12, 2017)

                Author contributions: L.E.C. and B.A.B. designed research; L.E.C., S.A.L., C.C., A.E.M., and M.H. performed research; M.H. contributed new reagents/analytic tools; L.E.C. and S.A.L. analyzed data; and L.E.C. and B.A.B. wrote the paper.

                2Deceased December 27, 2017.

                Article
                201800165
                10.1073/pnas.1800165115
                5828643
                29437957
                14d46799-86d4-4d56-a2b5-d134e3adff73
                Copyright © 2018 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 10
                Funding
                Funded by: HHS | NIH | National Institute on Aging (NIA) 100000049
                Award ID: RO1AG048814
                Funded by: JPB Foundation 100007457
                Award ID: NA
                Funded by: Glenn Foundation for Medical Research 100001642
                Award ID: NA
                Funded by: Australian National Health and Medical Research Council
                Award ID: GNT1052961
                Funded by: European Molecular Biology Organization (EMBO) 100004410
                Award ID: Long-term Fellowship
                Funded by: Life Sciences Research Foundation (LSRF) 100009559
                Award ID: Merck Research Laboratories postdoctoral fellowship
                Categories
                PNAS Plus
                Biological Sciences
                Neuroscience
                PNAS Plus

                astrocytes,aging,microglia,rna sequencing,cognitive decline
                astrocytes, aging, microglia, rna sequencing, cognitive decline

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