Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.11851/11621
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dc.contributor.authorİş, Özkan-
dc.contributor.authorWang, Xue-
dc.contributor.authorReddy, Joseph S.-
dc.contributor.authorMin, Yuhao-
dc.contributor.authorYılmaz, Elanur-
dc.contributor.authorBhattarai, Prabesh-
dc.contributor.authorPatel, Tulsi-
dc.date.accessioned2024-07-21T18:45:40Z-
dc.date.available2024-07-21T18:45:40Z-
dc.date.issued2024-
dc.identifier.issn2041-1723-
dc.identifier.urihttps://doi.org/10.1038/s41467-024-48926-6-
dc.identifier.urihttps://hdl.handle.net/20.500.11851/11621-
dc.description.abstractTo uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer's disease, we performed single nucleus RNA sequencing in 24 Alzheimer's disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer's disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer's disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer's disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer's disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer's disease. Systematic studies are needed to discover molecular determinants of blood brain barrier dysfunction in Alzheimer's disease. This study identifies perturbed pericytic SMAD3-astrocytic VEGFA interactions as a potential driver of this dysfunction.en_US
dc.description.sponsorshipU.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) [RF AG051504, U01 AG046139, R01 AG061796, U19 AG074879, P30 AG062677, R01 AG054449, R01 AG075802, U19 AG069701, R01 LM012535, U01AG072177, U19 AG024904, P30 AG072976, U01 AG068057]; National Institutes of Health, National Institute on Aging [R01AG067501, RF1AG066107, R01AG072474]; NIA; Columbia University Schaefer Research Scholar Award; Taub Institute Grants for Emerging Research [ZEN-22-969810]; Alzheimer's Association Zenith Fellows Award; Mayo Clinic Center for Regenerative Biotherapeutics; Taub Institute for Research on Alzheimer's Disease [S10OD020056]; Office of the Director, National Institutes of Health [P30CA013696]; NIH/NCI Cancer Center [UL1TR001873]; National Center for Advancing Translational Sciences, National Institutes of Health [U01 AG024904]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [W81XWH-12-2-0012]; DOD ADNI (Department of Defense); National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd; Fujirebio; Janssen Alzheimer Immunotherapy Research & development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Merck Co., Inc.; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Takeda Pharmaceutical Company; Canadian Institutes of Health Research; ADNI clinical sites in Canada; Foundation for the National Institutes of Health; Northern California Institute for Research and Education; Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu)en_US
dc.description.sponsorshipWe would like to thank the patients and their families for their participation, without whom these studies would not have been possible. This work was supported by the National Institutes of Health, National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796, U19 AG074879 to NET; P30 AG062677 to RCP, CJ, KK, MEM; R01 AG054449, R01 AG075802, U19 AG069701 to MEM; R01 LM012535 and U01AG072177 to KN; U19 AG024904, P30 AG072976, U01 AG068057, to AJS; NIA R01AG067501, RF1AG066107, R01AG072474 to RM, BNV, CK], Columbia University Schaefer Research Scholar Award, Thompson Family Foundation Program for Accelerated Medicines Exploration in Alzheimer's Disease and Related Disorders of The Nervous System (TAME-AD), and Taub Institute Grants for Emerging Research (TIGER) to C.K. NET is also supported by the Alzheimer's Association Zenith Fellows Award (ZEN-22-969810). We thank the Mayo Clinic Genome Analysis Core (GAC), Co-Directors, Julie M. Cunningham, PhD and Eric Wieben, PhD, and supervisor Julie Lau, for their collaboration in collection of omics data. We would like to thank the Mayo Clinic Center for Regenerative Biotherapeutics for providing iPSC lines and relevant patient data. We would like to thank Taub Institute for Research on Alzheimer's Disease and the Aging Brain Imaging Platform at Columbia University, Molecular Pathology (MPSR) and Flow Cytometry Core Facility (CCTI, supported in part by the Office of the Director, National Institutes of Health under awards S10OD020056) platforms of the Columbia University Herbert Irving Comprehensive Cancer Center for procedural support, and New York Brain Bank for post-mortem human brain sections. The single cell sequencing for zebrafish was performed by the Single Cell Analysis Core and Columbia Genome Center at the Sulzberger Genome Center, which was funded in part through the NIH/NCI Cancer Center Support Grant P30CA013696 and used the Genomics and High Throughput Screening Shared Resource. Part of the data generation for this publication at Columbia University was also supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org).; The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.en_US
dc.language.isoenen_US
dc.publisherNature portfolioen_US
dc.relation.ispartofNature Communicationsen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectEndothelial Growth-Factoren_US
dc.subjectCell Hipsc Linesen_US
dc.subjectGene-Expressionen_US
dc.subjectAngiogenesisen_US
dc.subjectGenerationen_US
dc.subjectNeurodegenerationen_US
dc.subjectBiomarkersen_US
dc.subjectDementiaen_US
dc.subjectCloningen_US
dc.subjectVegfen_US
dc.titleGliovascular Transcriptional Perturbations in Alzheimer's Disease Reveal Molecular Mechanisms of Blood Brain Barrier Dysfunctionen_US
dc.typeArticleen_US
dc.departmentTOBB ETÜen_US
dc.identifier.volume15en_US
dc.identifier.issue1en_US
dc.authoridYilmaz, Elanur/0000-0001-7045-5068-
dc.authoridOatman, Stephanie/0000-0001-8098-8677-
dc.authoridBergman, Jeremiah/0009-0009-1623-8703-
dc.identifier.wosWOS:001252057400014en_US
dc.identifier.scopus2-s2.0-85196642961en_US
dc.institutionauthor…-
dc.identifier.pmid38902234en_US
dc.identifier.doi10.1038/s41467-024-48926-6-
dc.authorwosidYilmaz, Elanur/I-8253-2017-
dc.authorscopusid57224004312-
dc.authorscopusid56477533700-
dc.authorscopusid55673931400-
dc.authorscopusid57225065802-
dc.authorscopusid56785228800-
dc.authorscopusid56613211700-
dc.authorscopusid57208099950-
dc.relation.publicationcategoryinfo:eu-repo/semantics/openAccessen_US
item.openairetypeArticle-
item.languageiso639-1en-
item.grantfulltextnone-
item.fulltextNo Fulltext-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
Appears in Collections:PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection
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