{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T07:05:37Z","timestamp":1792825537228,"version":"4.5.0"},"reference-count":74,"publisher":"National Academy of Sciences","issue":"47","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["R56AG073965"],"award-info":[{"award-number":["R56AG073965"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG065541"],"award-info":[{"award-number":["R01AG065541"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG071465"],"award-info":[{"award-number":["R01AG071465"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM007752"],"award-info":[{"award-number":["T32GM007752"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,11,23]]},"abstract":"<jats:p>\n                    Down syndrome (DS), trisomy of human chromosome 21 (HSA21), is characterized by lifelong cognitive impairments and the development of the neuropathological hallmarks of Alzheimer\u2019s disease (AD). The cellular and molecular modifications responsible for these effects are not understood. Here we performed single-nucleus RNA sequencing (snRNA-seq) employing both short- (Illumina) and long-read (Pacific Biosciences) sequencing technologies on a total of 29 DS and non-DS control prefrontal cortex samples. In DS, the ratio of inhibitory-to-excitatory neurons was significantly increased, which was not observed in previous reports examining sporadic AD. DS microglial transcriptomes displayed AD-related aging and activation signatures in advance of AD neuropathology, with increased microglial expression of C1q complement genes (associated with dendritic pruning) and the HSA21 transcription factor gene\n                    <jats:italic>RUNX1<\/jats:italic>\n                    . Long-read sequencing detected vast RNA isoform diversity within and among specific cell types, including numerous sequences that differed between DS and control brains. Notably, over 8,000 genes produced RNAs containing intra-exonic junctions, including amyloid precursor protein (\n                    <jats:italic>APP<\/jats:italic>\n                    ) that had previously been associated with somatic gene recombination. These and related results illuminate large-scale cellular and transcriptomic alterations as features of the aging DS brain.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2114326118","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T16:50:38Z","timestamp":1637254238000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":96,"title":["Altered cell and RNA isoform diversity in aging Down syndrome brains"],"prefix":"10.1073","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2385-2068","authenticated-orcid":false,"given":"Carter R.","family":"Palmer","sequence":"first","affiliation":[{"name":"Translational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;"},{"name":"Biomedical Sciences Program, School of Medicine, University of California San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1239-4612","authenticated-orcid":false,"given":"Christine S.","family":"Liu","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;"},{"name":"Biomedical Sciences Program, School of Medicine, University of California San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3808-6482","authenticated-orcid":false,"given":"William J.","family":"Romanow","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Hsiang","family":"Lee","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3964-0921","authenticated-orcid":false,"given":"Jerold","family":"Chun","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2021,11,18]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20735"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/s11689-017-9220-y"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410170310"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2011.11.001"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2017.00054"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.01081"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0078561"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau1810"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3983"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0718-6"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4038"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1506-7"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1195-2"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav8130"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1404-z"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.01.042"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2007.08.005"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2018.00012"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.05.004"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00285-9"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1850-9"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3314"},{"key":"e_1_3_5_24_2","article-title":"Single cell ATAC-seq identifies broad changes in neuronal abundance and chromatin accessibility in Down Syndrome","author":"Spektor R.","year":"2019","unstructured":"R. Spektor, J. W. Yang, S. Lee, P. D. Soloway, Single cell ATAC-seq identifies broad changes in neuronal abundance and chromatin accessibility in Down Syndrome. bioRxiv [Preprint] (2019). https:\/\/www.biorxiv.org\/content\/10.1101\/561191v1 (Accessed 15 March 2021).","journal-title":"bioRxiv"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0654-5"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.008078"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12273-8"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2013.04.004"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1713548114"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5725-09.2010"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4872-08.2009"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1714-14.2015"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1055"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1038"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/35058515"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a001941"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3037702"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4402"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0924-x"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.28080"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.018"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.036"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz2288"},{"key":"e_1_3_5_45_2","article-title":"A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding","author":"Li T.","year":"2020","unstructured":"T. Li , A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding. bioRxiv [Preprint] (2020). https:\/\/www.biorxiv.org\/content\/10.1101\/2020.04.24.059840v (Accessed 13 March 2021).","journal-title":"bioRxiv"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2777-8"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.09.010"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060482"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm086"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098992"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2015.04.008"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0059250"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00239"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-04-426247"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/1347969"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4259"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20343-5"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.239137.118"},{"key":"e_1_3_5_59_2","article-title":"A technology-agnostic long-read analysis pipeline for transcriptome discovery and quantification","author":"Wyman D.","year":"2020","unstructured":"D. Wyman , A technology-agnostic long-read analysis pipeline for transcriptome discovery and quantification. bioRxiv [Preprint] (2020). https:\/\/www.biorxiv.org\/content\/10.1101\/672931v1 (Accessed 23 January 2020).","journal-title":"bioRxiv"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2017.148"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.110"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02028-w"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.440"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.439"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2017.28"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(97)00045-4"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.039"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0242-x"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4515-09.2010"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3541"},{"key":"e_1_3_5_71_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1766-04.2004"},{"key":"e_1_3_5_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(99)00083-0"},{"key":"e_1_3_5_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0387-7604(01)00239-X"},{"key":"e_1_3_5_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2015.3"}],"updated-by":[{"DOI":"10.1073\/pnas.2212181119","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.2114326118","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2114326118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T13:58:36Z","timestamp":1662731916000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2114326118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,18]]},"references-count":74,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2021,11,23]]}},"alternative-id":["10.1073\/pnas.2114326118"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2114326118","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,18]]},"assertion":[{"value":"2021-08-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2114326118"}}