ArticleNature communications2024
Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction.
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Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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35citing papers in PubMed, 1 pooled it
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Pooled it
- Border-Associated Macrophage Migrasomes in Alzheimer's Disease: An Emerging Aβ-Senescence-Microglia Axis?Cells · 2026Review
- Single-cell transcriptomics of human brain disorders.Molecular psychiatry · 2026Review
- A meta-refined human Alzheimer's disease-associated gene subset shows partial mouse-model pathway correspondence and limited cross-cohort machine-learning transportability.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Fibronectin mediates APOE4-driven blood-brain barrier dysfunction in Alzheimer's disease.Nature aging · 2026Article
- Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer's disease.Acta neuropathologica · 2026Article
- Friend or foe? Glial-vascular interactions in health and neurodegenerative disease.Pharmacological reviews · 2026Review
- Contributions of the Alzheimer's Disease Neuroimaging Initiative to advancing AD research: a targeted review of recent publications.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Single-Nucleus Profiling Reveals a BBB Senescence Unit Driving AD Pathology in Human Brain.Molecular neurobiology · 2026Article
- Integrated imaging and molecular profiling reveals APOE4-associated neurovascular and glial disruptions in young adult mice.Journal of neuroinflammation · 2026Article
- Genetic correlation analysis of Alzheimer's disease and stroke implicates PHLPP1 as a shared locus in individuals of African ancestry.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Integrative epigenomic landscape of Alzheimer's Disease brains reveals oligodendrocyte molecular perturbations associated with tau.Nature communications · 2026Article
- Systems biology of Alzheimer's Disease: a scoping review of key pathways and mechanisms.Molecular neurodegeneration · 2026Article
- Isogenic cortical organoids enable precision targeting of APP variant-specific pathways in Alzheimer's disease.bioRxiv : the preprint server for biology · 2026Article
- Harnessing induced pluripotent stem cells and organoids for disease modeling and precision medicine.Stem cell research & therapy · 2026Review
- Brain Endothelial Glycocalyx as a Blood-Facing Translational Interface in Alzheimer's Disease: Beyond "Leaky" Barriers Toward Repair-First Stratification.Drug design, development and therapy · 2026Review
- Stage-Dependent Function of Astrocytes in Alzheimer's Disease: A Review.Neuroscience insights · 2026Review
- Astrocyte-blood-brain barrier crosstalk in cerebral small vessel disease: linking barrier dysfunction to neurovascular failure.Frontiers in neurology · 2026Review
- Mild traumatic brain injury promotes chronic cerebrovascular inflammation and glymphatic suppression.Molecular neurodegeneration advances · 2026Article
- Blood-brain barrier dysfunction and peripheral immune activation in Alzheimer's disease: an inflammation-centered review.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
41 authors.
Özkan İş *Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0003-4070-6756
Xue Wang *Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0003-1964-4124
Joseph S ReddyDepartment of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0002-1783-4453
Yuhao MinDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0001-8775-8743
Elanur YilmazDepartment of Neurology, Columbia University Irving Medical Center, New York, NY, USA.ORCID http://orcid.org/0000-0001-7045-5068
Prabesh BhattaraiDepartment of Neurology, Columbia University Irving Medical Center, New York, NY, USA.ORCID http://orcid.org/0000-0003-2991-5514
Tulsi PatelDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Jeremiah BergmanDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Zachary QuicksallDepartment of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0002-8791-0925
Michael G HeckmanDepartment of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.
Frederick Q Tutor-NewDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Birsen Can DemirdogenDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0002-1536-6123
Launia WhiteDepartment of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.
Shunsuke KogaDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0001-8868-9700
Vincent KrauseDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Yasuteru InoueDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Takahisa KanekiyoDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0001-6751-9374
Mehmet Ilyas CosacakGerman Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Dresden, Germany.ORCID http://orcid.org/0000-0003-2978-3902
Nastasia NelsonDepartment of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
Annie J LeeDepartment of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
Badri VardarajanDepartment of Neurology, Columbia University Irving Medical Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-5560-4085
Richard MayeuxDepartment of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
Naomi KouriDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0002-6841-9882
Kaancan DenizDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0002-5496-0598
Troy CarnwathDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Stephanie R OatmanDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Laura J Lewis-TuffinMayo Clinic Florida Cytometry and Cell Imaging Laboratory, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0002-6013-8322
Thuy NguyenDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0001-8879-7090
Alzheimer’s Disease Neuroimaging Initiative
Minerva M CarrasquilloDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0002-3231-9134
Jonathan Graff-RadfordDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.
Ronald C PetersenDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.ORCID http://orcid.org/0000-0002-8178-6601
Clifford R Jr JackMayo Clinic, Radiology, Rochester, MN, USA.ORCID http://orcid.org/0000-0001-7916-622X
Kejal KantarciMayo Clinic Alzheimer's Disease Research Center, Rochester, MN, USA.
Melissa E MurrayDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0001-7379-2545
Kwangsik NhoCenter for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
Andrew J SaykinDepartment of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.ORCID http://orcid.org/0000-0002-1376-8532
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0001-7189-7917
Caghan KizilDepartment of Neurology, Columbia University Irving Medical Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-8164-9762
Mariet AllenDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0002-2685-427X
Nilüfer Ertekin-TanerDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. taner.nilufer@mayo.edu.ORCID http://orcid.org/0000-0003-4436-8889
Funding
Project 1U19AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · PI MONICA G. RIVERA-MINDT · 2016 to 2026
$226.7MThe Health & Aging Brain Study - Health Disparities (HABS-HD)U19AG078109 · NIA · UNIVERSITY OF NORTH TEXAS HLTH SCI CTR · PI LEIGH A JOHNSON · 2022 to 2026
$181.1MAlzheimer's Disease Neuroimaging Initiative - SupplementU01AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE RES &EDUC · PI WEINER, MICHAEL W · 2004 to 2015
$121.0MTumor Biology and Microenvironment ProgramP30CA013696 · NCI · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI Anil K Rustgi · 1985 to 2026
$115.3MClinical and Translational Science AwardUL1TR001873 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI REILLY, MUREDACH P · 2016 to 2025
$99.0MPeripheral and Central Biomarkers of Alzheimer's Disease in Diverse CohortsU19AG074879 · NIA · MAYO CLINIC JACKSONVILLE · PI Minerva Maria Carrasquillo, NILUFER ERTEKIN-TANER · 2023 to 2026
$42.0MProject 4 (Genetic modifiers for APOE-associated Alzheimer's disease pathogenesis)U19AG069701 · NIA · MAYO CLINIC JACKSONVILLE · PI ALISON M GOATE, DAVID M. HOLTZMAN · 2021 to 2026
$42.0MResearch Education ComponentP30AG062677 · NIA · MAYO CLINIC ROCHESTER · PI John Lucas · 2019 to 2026
$33.5MResearch Education CoreP30AG066462 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI PHILIP L DE JAGER · 2020 to 2026
$30.1MIntegrating the exposome and methylome to inform brain molecular changes in ADRD across established diverse cohorts.U01AG046139 · NIA · UNIVERSITY OF FLORIDA · PI ERTEKIN-TANER, NILUFER, FUNK, CORY · 2013 to 2022
$24.6MResearch Education ComponentP30AG072976 · NIA · INDIANA UNIVERSITY INDIANAPOLIS · PI ANDREW J SAYKIN · 2021 to 2026
$24.1MUltrascale Machine Learning to Empower Discovery in Alzheimers Disease BiobanksU01AG068057 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Christos Davatzikos, Heng Huang · 2020 to 2026
$20.7MAlzheimer's Association ZEN-22-969810NCATS NIH HHS UL1 TR001873NCI NIH HHS P30 CA013696NIA NIH HHS K01 AG084849NIA NIH HHS P30 AG062677NIA NIH HHS P30 AG066462NIA NIH HHS P30 AG072976NIA NIH HHS R01 AG054449NIA NIH HHS R01 AG060477NIA NIH HHS R01 AG061796NIA NIH HHS R01 AG067501NIA NIH HHS R01 AG072474NIA NIH HHS R01 AG075802NIA NIH HHS RF1 AG051504NIA NIH HHS RF1 AG066107NIA NIH HHS U01 AG024904NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG068057NIA NIH HHS U01 AG072177NIA NIH HHS U19 AG024904NIA NIH HHS U19 AG069701NIA NIH HHS U19 AG074879NIA NIH HHS U19 AG078109NIH HHS S10 OD020056NLM NIH HHS R01 LM012535U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG067501U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG072474U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) RF1AG066107U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) RF AG051504U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) U01AG072177
Abstract
To 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.
Indexed as
Alzheimer DiseaseAstrocytesBlood-Brain BarrierPericytesSmad3 ProteinVascular Endothelial Growth Factor AZebrafishAgedAged, 80 and overAnimalsBrainDisease Models, AnimalFemaleHumansInduced Pluripotent Stem CellsMaleSmad3 ProteinSMAD3 protein, humanVascular Endothelial Growth Factor AVEGFA protein, human
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