{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T05:18:10Z","timestamp":1794028690677,"version":"4.8.0"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T00:00:00Z","timestamp":1722816000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T00:00:00Z","timestamp":1722816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG082127"],"award-info":[{"award-number":["R01 AG082127"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["U01 AG076791"],"award-info":[{"award-number":["U01 AG076791"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG067153"],"award-info":[{"award-number":["R01 AG067153"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["U54 AG054349"],"award-info":[{"award-number":["U54 AG054349"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["RF1 AG065675"],"award-info":[{"award-number":["RF1 AG065675"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"DOI":"10.13039\/100000055","name":"U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["T32 DC010775-14"],"award-info":[{"award-number":["T32 DC010775-14"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>The R47H missense mutation of the TREM2 gene is a known risk factor for development of Alzheimer\u2019s Disease. In this study, we analyze the impact of the <jats:italic>Trem2<\/jats:italic>\n            <jats:sup>R47H<\/jats:sup> mutation on specific cell types in multiple cortical and subcortical brain regions in the context of wild-type and 5xFAD mouse background. We profile 19 mouse brain sections consisting of wild-type, <jats:italic>Trem2<\/jats:italic>\n            <jats:sup>R47H<\/jats:sup>, 5xFAD and <jats:italic>Trem2<\/jats:italic>\n            <jats:sup>R47H<\/jats:sup>; 5xFAD genotypes using MERFISH spatial transcriptomics, a technique that enables subcellular profiling of spatial gene expression. Spatial transcriptomics and neuropathology data are analyzed using our custom pipeline to identify plaque and <jats:italic>Trem2<\/jats:italic>\n            <jats:sup>R47H<\/jats:sup>-induced transcriptomic dysregulation. We initially analyze\u00a0cell type-specific transcriptomic alterations induced by plaque proximity. Next, we analyze spatial distributions of disease associated microglia and astrocytes, and how they vary between 5xFAD and <jats:italic>Trem2<\/jats:italic>\n            <jats:sup>R47H<\/jats:sup>; 5xFAD mouse models. Finally, we analyze the impact of the <jats:italic>Trem2<\/jats:italic>\n            <jats:sup>R47H<\/jats:sup> mutation\u00a0on neuronal transcriptomes. The <jats:italic>Trem2<\/jats:italic>\n            <jats:sup>R47H<\/jats:sup> mutation induces consistent upregulation of <jats:italic>Bdnf<\/jats:italic> and <jats:italic>Ntrk2<\/jats:italic> across many cortical excitatory neuron types, independent of amyloid pathology. Spatial investigation of genotype enriched subclusters identified spatially localized neuronal subpopulations reduced in 5xFAD and <jats:italic>Trem2<\/jats:italic>\n            <jats:sup>R47H<\/jats:sup>; 5xFAD mice. Overall, our MERFISH spatial transcriptomics analysis identifies glial and neuronal transcriptomic alterations induced independently by 5xFAD and <jats:italic>Trem2<\/jats:italic>\n            <jats:sup>R47H<\/jats:sup> mutations, impacting inflammatory responses in microglia and astrocytes, and activity and BDNF signaling in neurons.<\/jats:p>","DOI":"10.1038\/s41380-024-02651-0","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T19:02:46Z","timestamp":1722884566000},"page":"461-477","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Single-cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Trem2R47H Alzheimer\u2019s risk gene mutation"],"prefix":"10.1038","volume":"30","author":[{"given":"Kevin G.","family":"Johnston","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bereket T.","family":"Berackey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine M.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alon","family":"Gelber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoxia","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant R.","family":"MacGregor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3203-9535","authenticated-orcid":false,"given":"Eran A.","family":"Mukamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2235-4577","authenticated-orcid":false,"given":"Zhiqun","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6049-6744","authenticated-orcid":false,"given":"Kim N.","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5828-1533","authenticated-orcid":false,"given":"Xiangmin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,5]]},"reference":[{"key":"2651_CR1","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1038\/s41588-021-00921-z","volume":"53","author":"DP Wightman","year":"2021","unstructured":"Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer\u2019s disease. Nat Genet. 2021;53:1276\u201382.","journal-title":"Nat Genet"},{"key":"2651_CR2","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1056\/NEJMoa1211851","volume":"368","author":"R Guerreiro","year":"2013","unstructured":"Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer\u2019s disease. N Engl J Med. 2013;368:117\u201327.","journal-title":"N Engl J Med"},{"key":"2651_CR3","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1056\/NEJMoa1211103","volume":"368","author":"T Jonsson","year":"2013","unstructured":"Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer\u2019s disease. N Engl J Med. 2013;368:107\u201316.","journal-title":"N Engl J Med"},{"key":"2651_CR4","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1046\/j.1471-4159.2002.01243.x","volume":"83","author":"CD Schmid","year":"2002","unstructured":"Schmid CD, Sautkulis LN, Danielson PE, Cooper J, Hasel KW, Hilbush BS, et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells\u20102 on adult murine microglia. J Neurochem. 2002;83:1309\u201320.","journal-title":"J Neurochem"},{"key":"2651_CR5","doi-asserted-by":"crossref","first-page":"4991","DOI":"10.4049\/jimmunol.164.10.4991","volume":"164","author":"A Bouchon","year":"2000","unstructured":"Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000;164:4991\u20135.","journal-title":"J Immunol"},{"key":"2651_CR6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-018-0298-9","volume":"13","author":"M Gratuze","year":"2018","unstructured":"Gratuze M, Leyns CE, Holtzman DM. New insights into the role of TREM2 in Alzheimer\u2019s disease. Mol Neurodegener. 2018;13:1\u201316.","journal-title":"Mol Neurodegener"},{"key":"2651_CR7","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.cell.2015.01.049","volume":"160","author":"Y Wang","year":"2015","unstructured":"Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer\u2019s disease model. Cell. 2015;160:1061\u201371.","journal-title":"Cell"},{"key":"2651_CR8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.jalz.2016.07.004","volume":"13","author":"W Song","year":"2017","unstructured":"Song W, Hooli B, Mullin K, Jin SC, Cella M, Ulland TK, et al. Alzheimer\u2019s disease\u2010associated TREM2 variants exhibit either decreased or increased ligand\u2010dependent activation. Alzheimer\u2019s Dement. 2017;13:381\u20137.","journal-title":"Alzheimer\u2019s Dement"},{"key":"2651_CR9","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41582-020-00435-y","volume":"17","author":"F Leng","year":"2021","unstructured":"Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17:157\u201372.","journal-title":"Nat Rev Neurol"},{"key":"2651_CR10","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.abe3947","volume":"13","author":"FA Sayed","year":"2021","unstructured":"Sayed FA, Kodama L, Fan L, Carling GK, Udeochu JC, Le D, et al. AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation. Sci Transl Med. 2021;13:eabe3947.","journal-title":"Sci Transl Med"},{"key":"2651_CR11","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-11674-z","volume":"10","author":"E Spangenberg","year":"2019","unstructured":"Spangenberg E, Severson PL, Hohsfield LA, Crapser J, Zhang J, Burton EA, et al. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer\u2019s disease model. Nat Commun. 2019;10:3758.","journal-title":"Nat Commun"},{"key":"2651_CR12","doi-asserted-by":"crossref","DOI":"10.1016\/j.nbd.2020.104956","volume":"142","author":"BT Casali","year":"2020","unstructured":"Casali BT, MacPherson KP, Reed-Geaghan EG, Landreth GE. Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies. Neurobiol Dis. 2020;142:104956.","journal-title":"Neurobiol Dis"},{"key":"2651_CR13","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms7176","volume":"6","author":"C Condello","year":"2015","unstructured":"Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar A\u03b242 hotspots around plaques. Nat Commun. 2015;6:6176.","journal-title":"Nat Commun"},{"key":"2651_CR14","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1084\/jem.20190980","volume":"216","author":"Y Shi","year":"2019","unstructured":"Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019;216:2546\u201361.","journal-title":"J Exp Med"},{"key":"2651_CR15","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abg1601","volume":"7","author":"MA Arreola","year":"2021","unstructured":"Arreola MA, Soni N, Crapser JD, Hohsfield LA, Elmore MR, Matheos DP, et al. Microglial dyshomeostasis drives perineuronal net and synaptic loss in a CSF1R+\/\u2212 mouse model of ALSP, which can be rescued via CSF1R inhibitors. Sci Adv. 2021;7:eabg1601.","journal-title":"Sci Adv"},{"key":"2651_CR16","doi-asserted-by":"crossref","first-page":"102919","DOI":"10.1016\/j.ebiom.2020.102919","volume":"58","author":"JD Crapser","year":"2020","unstructured":"Crapser JD, Spangenberg EE, Barahona RA, Arreola MA, Hohsfield LA, Green KN. Microglia facilitate loss of perineuronal nets in the Alzheimer\u2019s disease brain. EBioMedicine. 2020;58:102919.","journal-title":"EBioMedicine"},{"key":"2651_CR17","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1126\/science.aad8373","volume":"352","author":"S Hong","year":"2016","unstructured":"Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712\u20136.","journal-title":"Science"},{"key":"2651_CR18","doi-asserted-by":"crossref","first-page":"9977","DOI":"10.1523\/JNEUROSCI.0336-15.2015","volume":"35","author":"RA Rice","year":"2015","unstructured":"Rice RA, Spangenberg EE, Yamate-Morgan H, Lee RJ, Arora RP, Hernandez MX, et al. Elimination of microglia improves functional outcomes following extensive neuronal loss in the hippocampus. J Neurosci. 2015;35:9977\u201389.","journal-title":"J Neurosci"},{"key":"2651_CR19","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1126\/science.aaz2288","volume":"367","author":"C Wang","year":"2020","unstructured":"Wang C, Yue H, Hu Z, Shen Y, Ma J, Li J, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science. 2020;367:688\u201394.","journal-title":"Science"},{"key":"2651_CR20","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.immuni.2019.12.004","volume":"52","author":"S Werneburg","year":"2020","unstructured":"Werneburg S, Jung J, Kunjamma RB, Ha S-K, Luciano NJ, Willis CM, et al. Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease. Immunity. 2020;52:167\u201382.","journal-title":"Immunity"},{"key":"2651_CR21","first-page":"792","volume":"140","author":"Z Fan","year":"2017","unstructured":"Fan Z, Brooks DJ, Okello A, Edison P. An early and late peak in microglial activation in Alzheimer\u2019s disease trajectory. Brain. 2017;140:792\u2013803.","journal-title":"Brain"},{"key":"2651_CR22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-022-00590-4","volume":"18","author":"KM Tran","year":"2023","unstructured":"Tran KM, Kawauchi S, Kram\u00e1r EA, Rezaie N, Liang HY, Sakr JS, et al. A Trem2R47H mouse model without cryptic splicing drives age-and disease-dependent tissue damage and synaptic loss in response to plaques. Mol Neurodegeneration. 2023;18:1\u201326.","journal-title":"Mol Neurodegeneration"},{"key":"2651_CR23","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.tins.2007.07.007","volume":"30","author":"JM Pocock","year":"2007","unstructured":"Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007;30:527\u201335.","journal-title":"Trends Neurosci"},{"key":"2651_CR24","first-page":"430","volume":"26","author":"H Zeng","year":"2023","unstructured":"Zeng H, Huang J, Zhou H, Meilandt WJ, Dejanovic B, Zhou Y, et al. Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer\u2019s disease. Nat Neurosci. 2023;26:430\u201346.","journal-title":"Nat Neurosci"},{"key":"2651_CR25","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","volume":"26","author":"H Oakley","year":"2006","unstructured":"Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal \u03b2-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer\u2019s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129\u201340.","journal-title":"J Neurosci"},{"key":"2651_CR26","doi-asserted-by":"crossref","DOI":"10.3389\/fnagi.2021.713726","volume":"13","author":"AL Oblak","year":"2021","unstructured":"Oblak AL, Lin PB, Kotredes KP, Pandey RS, Garceau D, Williams HM, et al. Comprehensive evaluation of the 5XFAD mouse model for preclinical testing applications: a MODEL-AD study. Front Aging Neurosci. 2021;13:713726.","journal-title":"Front Aging Neurosci"},{"key":"2651_CR27","doi-asserted-by":"crossref","DOI":"10.1038\/s41597-021-01054-y","volume":"8","author":"S Forner","year":"2021","unstructured":"Forner S, Kawauchi S, Balderrama-Gutierrez G, Kram\u00e1r EA, Matheos DP, Phan J, et al. Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer\u2019s disease. Sci Data. 2021;8:270.","journal-title":"Sci Data"},{"key":"2651_CR28","doi-asserted-by":"crossref","unstructured":"Yao Z, van Velthoven CTJ, Kunst M, Zhang M, McMillen D, Lee C, et al. A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain. Nature 2023;624:317\u201332.","DOI":"10.1038\/s41586-023-06812-z"},{"key":"2651_CR29","doi-asserted-by":"crossref","unstructured":"Zhang M, Pan X, Jung W, Halpern AR, Eichhorn SW, Lei Z, et al. Molecularly defined and spatially resolved cell atlas of the whole mouse brain. Nature 2023;624:343\u201354.","DOI":"10.1038\/s41586-023-06808-9"},{"key":"2651_CR30","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.cell.2022.12.010","volume":"186","author":"WE Allen","year":"2023","unstructured":"Allen WE, Blosser TR, Sullivan ZA, Dulac C, Zhuang X. Molecular and spatial signatures of mouse brain aging at single-cell resolution. Cell. 2023;186:194\u2013208.e118.","journal-title":"Cell"},{"key":"2651_CR31","doi-asserted-by":"crossref","first-page":"6171","DOI":"10.1523\/JNEUROSCI.0601-22.2022","volume":"42","author":"PA Feinberg","year":"2022","unstructured":"Feinberg PA, Becker SC, Chung L, Ferrari L, Stellwagen D, Anaclet C, et al. Elevated TNF-\u03b1 leads to neural circuit instability in the absence of Interferon Regulatory Factor 8. J Neurosci. 2022;42:6171\u201385.","journal-title":"J Neurosci"},{"key":"2651_CR32","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1002\/alz.12821","volume":"19","author":"EL Castranio","year":"2023","unstructured":"Castranio EL, Hasel P, Haure-Mirande JV, Ramirez Jimenez AV, Hamilton BW, Kim RD, et al. Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer\u2019s disease. Alzheimer\u2019s Dement. 2023;19:2239\u201352.","journal-title":"Alzheimer\u2019s Dement"},{"key":"2651_CR33","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.cell.2020.06.038","volume":"182","author":"W-T Chen","year":"2020","unstructured":"Chen W-T, Lu A, Craessaerts K, Pavie B, Frigerio CS, Corthout N, et al. Spatial transcriptomics and in situ sequencing to study Alzheimer\u2019s disease. Cell. 2020;182:976\u201391.e919.","journal-title":"Cell"},{"key":"2651_CR34","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/s41592-020-01018-x","volume":"18","author":"C Stringer","year":"2021","unstructured":"Stringer C, Wang T, Michaelos M, Pachitariu M. Cellpose: a generalist algorithm for cellular segmentation. Nat Methods. 2021;18:100\u20136.","journal-title":"Nat Methods"},{"key":"2651_CR35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-017-1381-1","volume":"19","author":"FA Wolf","year":"2018","unstructured":"Wolf FA, Angerer P, Theis FJ. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 2018;19:1\u20135.","journal-title":"Genome Biol"},{"key":"2651_CR36","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","volume":"16","author":"I Korsunsky","year":"2019","unstructured":"Korsunsky I, Millard N, Fan J, Slowikowski K, Zhang F, Wei K, et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods. 2019;16:1289\u201396.","journal-title":"Nat Methods"},{"key":"2651_CR37","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1016\/j.cell.2021.04.021","volume":"184","author":"Z Yao","year":"2021","unstructured":"Yao Z, van Velthoven CT, Nguyen TN, Goldy J, Sedeno-Cortes AE, Baftizadeh F, et al. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell. 2021;184:3222\u201341.e3226.","journal-title":"Cell"},{"key":"2651_CR38","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.cell.2018.06.021","volume":"174","author":"A Zeisel","year":"2018","unstructured":"Zeisel A, Hochgerner H, L\u00f6nnerberg P, Johnsson A, Memic F, Van Der Zwan J, et al. Molecular architecture of the mouse nervous system. Cell. 2018;174:999\u20131014.e1022.","journal-title":"Cell"},{"key":"2651_CR39","doi-asserted-by":"crossref","first-page":"D996","DOI":"10.1093\/nar\/gks1042","volume":"41","author":"SM Sunkin","year":"2012","unstructured":"Sunkin SM, Ng L, Lau C, Dolbeare T, Gilbert TL, Thompson CL, et al. Allen brain atlas: an integrated spatio-temporal portal for exploring the central nervous system. Nucleic Acids Res. 2012;41:D996\u2013D1008.","journal-title":"Nucleic Acids Res"},{"key":"2651_CR40","first-page":"2122","volume":"5","author":"AT Lun","year":"2016","unstructured":"Lun AT, McCarthy DJ, Marioni JC. A step-by-step workflow for low-level analysis of single-cell RNA-seq data with Bioconductor. F1000Research. 2016;5:2122.","journal-title":"F1000Research"},{"key":"2651_CR41","doi-asserted-by":"crossref","unstructured":"Murphy AE, Skene NG. A balanced measure shows superior performance of pseudobulk methods in single-cell RNA-sequencing analysis. Nat Commun. 2022;13:7851.","DOI":"10.1038\/s41467-022-35519-4"},{"key":"2651_CR42","doi-asserted-by":"crossref","unstructured":"Bates D, M\u00e4chler M, Bolker B, & Walker S. Fitting Linear Mixed-Effects Models Using lme4. J Stat Softw. 2015;67:1\u201348.","DOI":"10.18637\/jss.v067.i01"},{"key":"2651_CR43","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1002\/bimj.200810425","volume":"50","author":"T Hothorn","year":"2008","unstructured":"Hothorn T, Bretz F, Westfall P. Simultaneous inference in general parametric models. Biometrical J. 2008;50:346\u201363.","journal-title":"Biometrical J"},{"key":"2651_CR44","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289\u2013300.","journal-title":"J R Stat Soc Ser B"},{"key":"2651_CR45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/gb-2014-15-1-r1","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:1\u201321.","journal-title":"Genome Biol"},{"key":"2651_CR46","volume":"11","author":"JW Vogel","year":"2020","unstructured":"Vogel JW, La Joie R, Grothe MJ, Diaz-Papkovich A, Doyle A, Vachon-Presseau E, et al. A molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems. Nat Commun. 2020;11:960.","journal-title":"Nat Commun"},{"key":"2651_CR47","unstructured":"Bellock K. Alphashape. 2021."},{"key":"2651_CR48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-021-00511-x","volume":"17","author":"J Hou","year":"2022","unstructured":"Hou J, Chen Y, Grajales-Reyes G, Colonna M. TREM2 dependent and independent functions of microglia in Alzheimer\u2019s disease. Mol Neurodegener. 2022;17:1\u201319.","journal-title":"Mol Neurodegener"},{"key":"2651_CR49","doi-asserted-by":"crossref","unstructured":"Rajamohamedsait HB, Sigurdsson EM. Histological staining of amyloid and pre-amyloid peptides and proteins in mouse tissue. Amyloid Proteins Methods Protocols 2012: 411\u201324.","DOI":"10.1007\/978-1-61779-551-0_28"},{"key":"2651_CR50","doi-asserted-by":"crossref","first-page":"111686","DOI":"10.1016\/j.celrep.2022.111686","volume":"41","author":"JI Wood","year":"2022","unstructured":"Wood JI, Wong E, Joghee R, Balbaa A, Vitanova KS, Stringer KM, et al. Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology. Cell Rep. 2022;41:111686.","journal-title":"Cell Rep"},{"key":"2651_CR51","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.cell.2018.05.003","volume":"173","author":"A Deczkowska","year":"2018","unstructured":"Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell. 2018;173:1073\u201381.","journal-title":"Cell"},{"key":"2651_CR52","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41593-020-0624-8","volume":"23","author":"N Habib","year":"2020","unstructured":"Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D, Dvir-Szternfeld R, et al. Disease-associated astrocytes in Alzheimer\u2019s disease and aging. Nat Neurosci. 2020;23:701\u20136.","journal-title":"Nat Neurosci"},{"key":"2651_CR53","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1038\/s41592-022-01575-3","volume":"19","author":"DM Cable","year":"2022","unstructured":"Cable DM, Murray E, Shanmugam V, Zhang S, Zou LS, Diao M, et al. Cell type-specific inference of differential expression in spatial transcriptomics. Nat Methods. 2022;19:1076\u201387.","journal-title":"Nat Methods"},{"key":"2651_CR54","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1242\/dmm.028571","volume":"10","author":"D Martins","year":"2017","unstructured":"Martins D, Moreira J, Gon\u00e7alves NP, Saraiva MJ. MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy. Dis Models Mech. 2017;10:1253\u201360.","journal-title":"Dis Models Mech"},{"key":"2651_CR55","doi-asserted-by":"crossref","DOI":"10.3389\/fnins.2021.735928","volume":"15","author":"G Amadoro","year":"2021","unstructured":"Amadoro G, Latina V, Balzamino BO, Squitti R, Varano M, Calissano P, et al. Nerve growth factor-based therapy in Alzheimer\u2019s disease and age-related macular degeneration. Front Neurosci. 2021;15:735928.","journal-title":"Front Neurosci"},{"key":"2651_CR56","doi-asserted-by":"crossref","first-page":"e12244","DOI":"10.1002\/trc2.12244","volume":"8","author":"MW Lutz","year":"2022","unstructured":"Lutz MW, Chiba-Falek O. Bioinformatics pipeline to guide late-onset Alzheimer\u2019s disease (LOAD) post-GWAS studies: Prioritizing transcription regulatory variants within LOAD-associated regions. Alzheimer\u2019s Dement Transl Res Clin Intervent. 2022;8:e12244.","journal-title":"Alzheimer\u2019s Dement Transl Res Clin Intervent"},{"key":"2651_CR57","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.neulet.2019.03.050","volume":"704","author":"S Chakraborty","year":"2019","unstructured":"Chakraborty S, Lennon JC, Malkaram SA, Zeng Y, Fisher DW, Dong H. Serotonergic system, cognition, and BPSD in Alzheimer\u2019s disease. Neurosci Lett. 2019;704:36\u201344.","journal-title":"Neurosci Lett"},{"key":"2651_CR58","doi-asserted-by":"crossref","first-page":"733","DOI":"10.3233\/JAD-161254","volume":"60","author":"L Zhang","year":"2017","unstructured":"Zhang L, Sun C, Jin Y, Gao K, Shi X, Qiu W, et al. Dickkopf 3 (dkk3) improves amyloid-\u03b2 pathology, cognitive dysfunction, and cerebral glucose metabolism in a transgenic mouse model of Alzheimer\u2019s disease. J Alzheimer\u2019s Dis. 2017;60:733\u201346.","journal-title":"J Alzheimer\u2019s Dis"},{"key":"2651_CR59","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3389\/fncel.2019.00265","volume":"13","author":"W Noh","year":"2019","unstructured":"Noh W, Pak S, Choi G, Yang S, Yang S. Transient potassium channels: therapeutic targets for brain disorders. Front Cell Neurosci. 2019;13:265.","journal-title":"Front Cell Neurosci"},{"key":"2651_CR60","doi-asserted-by":"crossref","unstructured":"Skaper SD. The neurotrophin family of neurotrophic factors: an overview. Neurotrophic Factors Methods Protoc 2012: 1\u201312.","DOI":"10.1007\/978-1-61779-536-7_1"},{"key":"2651_CR61","doi-asserted-by":"crossref","first-page":"3437","DOI":"10.1093\/cercor\/bhx046","volume":"27","author":"DM Cummings","year":"2017","unstructured":"Cummings DM, Benway TA, Ho H, Tedoldi A, Fernandes Freitas MM, Shahab L, et al. Neuronal and peripheral pentraxins modify glutamate release and may interact in blood\u2013brain barrier failure. Cereb Cortex. 2017;27:3437\u201348.","journal-title":"Cereb Cortex"},{"key":"2651_CR62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13041-015-0166-2","volume":"8","author":"A Ghosh","year":"2015","unstructured":"Ghosh A, Giese KP. Calcium\/calmodulin-dependent kinase II and Alzheimer\u2019s disease. Mol Brain. 2015;8:1\u20137.","journal-title":"Mol Brain"},{"key":"2651_CR63","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","volume":"169","author":"H Keren-Shaul","year":"2017","unstructured":"Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A unique microglia type associated with restricting development of Alzheimer\u2019s disease. Cell. 2017;169:1276\u201390.e1217.","journal-title":"Cell"},{"key":"2651_CR64","doi-asserted-by":"crossref","first-page":"202","DOI":"10.4161\/19336918.2014.994919","volume":"9","author":"E Seong","year":"2015","unstructured":"Seong E, Yuan L, Arikkath J. Cadherins and catenins in dendrite and synapse morphogenesis. Cell Adhes Migr. 2015;9:202\u201313.","journal-title":"Cell Adhes Migr"},{"key":"2651_CR65","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jpsychires.2012.10.003","volume":"47","author":"Z Li","year":"2013","unstructured":"Li Z, Zhang Y, Wang Z, Chen J, Fan J, Guan Y, et al. The role of BDNF, NTRK2 gene and their interaction in development of treatment-resistant depression: data from multicenter, prospective, longitudinal clinic practice. J Psychiatr Res. 2013;47:8\u201314.","journal-title":"J Psychiatr Res"},{"key":"2651_CR66","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3389\/fnbeh.2018.00079","volume":"12","author":"FT Gallo","year":"2018","unstructured":"Gallo FT, Katche C, Morici JF, Medina JH, Weisstaub NV. Immediate early genes, memory and psychiatric disorders: focus on c-Fos, Egr1 and Arc. Front Behav Neurosci. 2018;12:79.","journal-title":"Front Behav Neurosci"},{"key":"2651_CR67","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.4103\/1673-5374.361540","volume":"18","author":"S Chen","year":"2023","unstructured":"Chen S, Acosta D, Fu H. New unexpected role for Wolfram Syndrome protein WFS1: a novel therapeutic target for Alzheimer\u2019s disease? Neural Regenerat Res. 2023;18:1501.","journal-title":"Neural Regenerat Res"},{"key":"2651_CR68","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3233\/ADR-170028","volume":"1","author":"RO Roberts","year":"2017","unstructured":"Roberts RO, Kang YN, Hu C, Moser CD, Wang S, Moore MJ, et al. Decreased expression of sulfatase 2 in the brains of Alzheimer\u2019s disease patients: Implications for regulation of neuronal cell signaling. J Alzheimer\u2019s Dis Rep. 2017;1:115\u201324.","journal-title":"J Alzheimer\u2019s Dis Rep"},{"key":"2651_CR69","doi-asserted-by":"crossref","first-page":"41652","DOI":"10.1074\/jbc.M205044200","volume":"277","author":"K Hu","year":"2002","unstructured":"Hu K, Carroll J, Rickman C, Davletov B. Action of complexin on SNARE complex. J Biol Chem. 2002;277:41652\u20136.","journal-title":"J Biol Chem"},{"key":"2651_CR70","doi-asserted-by":"crossref","DOI":"10.1093\/ijnp\/pyv106","volume":"19","author":"M Dines","year":"2016","unstructured":"Dines M, Lamprecht R. The role of ephs and ephrins in memory formation. Int J Neuropsychopharmacol. 2016;19:pyv106.","journal-title":"Int J Neuropsychopharmacol"},{"key":"2651_CR71","doi-asserted-by":"crossref","DOI":"10.3389\/fnagi.2022.831967","volume":"14","author":"AN McCorkindale","year":"2022","unstructured":"McCorkindale AN, Patrick E, Duce JA, Guennewig B, Sutherland GT. The key factors predicting dementia in individuals with Alzheimer\u2019s disease-type pathology. Front Aging Neurosci. 2022;14:831967.","journal-title":"Front Aging Neurosci"},{"key":"2651_CR72","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-021-00465-0","volume":"16","author":"MM Rahman","year":"2021","unstructured":"Rahman MM, Lendel C. Extracellular protein components of amyloid plaques and their roles in Alzheimer\u2019s disease pathology. Mol Neurodegener. 2021;16:1\u201330.","journal-title":"Mol Neurodegener"},{"key":"2651_CR73","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2021.660104","volume":"14","author":"H J\u0119\u015bko","year":"2021","unstructured":"J\u0119\u015bko H, Wieczorek I, Wencel PL, G\u0105ssowska-Dobrowolska M, Lukiw WJ, Strosznajder RP. Age-related transcriptional deregulation of genes coding synaptic proteins in Alzheimer\u2019s disease murine model: potential neuroprotective effect of fingolimod. Front Mol Neurosci. 2021;14:660104.","journal-title":"Front Mol Neurosci"},{"key":"2651_CR74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40035-021-00276-9","volume":"11","author":"L Gao","year":"2022","unstructured":"Gao L, Zhang Y, Sterling K, Song W. Brain-derived neurotrophic factor in Alzheimer\u2019s disease and its pharmaceutical potential. Transl Neurodegener. 2022;11:1\u201334.","journal-title":"Transl Neurodegener"},{"key":"2651_CR75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5607\/en.2020.29.1.1","volume":"29","author":"K Noh","year":"2020","unstructured":"Noh K, Park J-C, Han J-S, Lee SJ. From bound cells comes a sound mind: the role of neuronal growth regulator 1 in psychiatric disorders. Exp Neurobiol. 2020;29:1.","journal-title":"Exp Neurobiol"},{"key":"2651_CR76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1750-1326-7-13","volume":"7","author":"M Allen","year":"2012","unstructured":"Allen M, Zou F, Chai HS, Younkin CS, Miles R, Nair AA, et al. Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications. Mol Neurodegener. 2012;7:1\u201312.","journal-title":"Mol Neurodegener"},{"key":"2651_CR77","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1326-8-2","volume":"8","author":"WA Eimer","year":"2013","unstructured":"Eimer WA, Vassar R. Neuron loss in the 5XFAD mouse model of Alzheimer\u2019s disease correlates with intraneuronal A\u03b242 accumulation and Caspase-3 activation. Mol Neurodegener. 2013;8:2.","journal-title":"Mol Neurodegener"},{"key":"2651_CR78","volume":"218","author":"Y Chen","year":"2021","unstructured":"Chen Y, Colonna M. Microglia in Alzheimer\u2019s disease at single-cell level. Are there common patterns in humans and mice? J Exp Med. 2021;218:e20202717.","journal-title":"J Exp Med"},{"key":"2651_CR79","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41380-022-01915-x","volume":"28","author":"SF Grieco","year":"2023","unstructured":"Grieco SF, Holmes TC, Xu X. Probing neural circuit mechanisms in Alzheimer\u2019s disease using novel technologies. Mol Psychiatry. 2023;28:1\u201314.","journal-title":"Mol Psychiatry"},{"key":"2651_CR80","doi-asserted-by":"crossref","first-page":"5719","DOI":"10.3390\/ijms22115719","volume":"22","author":"T Numakawa","year":"2021","unstructured":"Numakawa T, Odaka H. Brain-derived neurotrophic factor signaling in the pathophysiology of Alzheimer\u2019s disease: Beneficial effects of flavonoids for neuroprotection. Int J Mol Sci. 2021;22:5719.","journal-title":"Int J Mol Sci"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-024-02651-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-024-02651-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-024-02651-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T19:32:32Z","timestamp":1737401552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-024-02651-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,5]]},"references-count":80,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["2651"],"URL":"https:\/\/doi.org\/10.1038\/s41380-024-02651-0","relation":{},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,5]]},"assertion":[{"value":"27 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 June 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 June 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 August 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study did not involve any human subjects. All animal care and related experimental procedures were conducted following the highest ethical standards and were approved by the UC Irvine Institutional Animal Care and Use Committee. All animals were bred and raised by the Transgenic Mouse Facility at UCI under a regular light\/dark (12\u2009h\/12\u2009h) cycle with ad libitum access to food and water.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}