ArticleCell reports2023
Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1.
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Article in Cell reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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36citing papers in PubMed, 1 pooled it
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36 citing papers in PubMed, 1 synthesis or guideline pooled it, 47 citations in OpenAlex.
- Review of the evidence on the influence of Wi-Fi 2.4 GHz radiation on oxidative stress and its possible relationship with Alzheimer's disease.Frontiers in neurology · 2025Pooled it
- SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain.Science advances · 2026Article
- The Role of Genetic Alterations in the Emergence of Alzheimer's Disease in Down Syndrome: A Review.The European journal of neuroscience · 2026Review
- HDL-mimetic peptide treatment reverses APOE4-induced transcriptomic and lipidomic alterations in the brain of humanized APOE mice.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Lipidomic and sterolomic profiles of different brain regions in the mouse model of Alzheimer's disease.Neural regeneration research · 2026Article
- Alzheimer's disease risk protein SorLA regulates ER homeostasis and lipid metabolism in human microglia, with conserved effects in neurons.Acta neuropathologica · 2026Article
- RhoGEF12 regulates endosomal SORL1-retromer and its inhibition is therapeutic in human neuronal models of Alzheimer's disease.bioRxiv : the preprint server for biology · 2026Article
- Computational Modelling and Clinical Validation of an Alzheimer's-Related Network in Brain Cancer: The SKM034 Model.Current issues in molecular biology · 2026Article
- Interpretable machine-learning prediction of PSEN1 missense variant pathogenicity based on multi-omics enrichment in six core Alzheimer's disease genes.Alzheimer's research & therapy · 2026Article
- Association between Alzheimer's disease-related genes and neurodegenerative blood-based biomarkers in Indian adults.Frontiers in aging neuroscience · 2026Article
- Autophagy-lysosomal pathway in neurodegeneration.Molecular neurodegeneration advances · 2026Review
- Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model.bioRxiv : the preprint server for biology · 2025Article
- Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis.Acta neuropathologica · 2025Article
- Optineurin deficiency disrupts phosphorylated tau proteostasis and clusterin expression in human neurons.Acta neuropathologica communications · 2025Article
- Clusterin Regulates the Mechanisms of Neuroinflammation and Neuronal Circuit Impairment in Alzheimer's Disease.International journal of molecular sciences · 2025Review
- Systems genetics reveals the influence of expression QTLs in mouse embryonic stem cells on transcriptional variation later in differentiated neural progenitor cells.G3 (Bethesda, Md.) · 2025Article
- Article
- Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures.Cell reports · 2025Article
- The APOE-Microglia Axis in Alzheimer's Disease: Functional Divergence and Therapeutic Perspectives-A Narrative Review.Brain sciences · 2025Review
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Authors and funding
22 authors at 8 institutions in 3 countries.
Hyo LeeAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Aimee J AylwardAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Richard V PearseAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Alexandra M LishAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Yi-Chen HsiehAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Zachary M AugurAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Courtney R BenoitAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Vicky ChouAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Allison KnuppDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
Cheryl PanAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Srilakshmi GoberdhanAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Duc M DuongDepartment of Biochemistry, Emory School of Medicine, Atlanta, GA, USA.
Nicholas T SeyfriedDepartment of Biochemistry, Emory School of Medicine, Atlanta, GA, USA.
David A BennettRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Mariko F TagaCenter for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
Kevin HuynhBaker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia.
Matthias ArnoldInstitute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
Peter J MeikleBaker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia.
Philip L De JagerCenter for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
Vilas MenonCenter for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
Jessica E YoungDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
Tracy L Young-PearseAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: tpearse@bwh.harvard.edu.
Brigham and Women's Hospital · USHarvard University · USColumbia University · USBaker Heart and Diabetes Institute · AUEmory University · USUniversity of Washington · USHelmholtz Zentrum München · DERush University Medical Center · US
Funding
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8MMulti-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targetsU01AG061356 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2018 to 2022
$13.7MMetabolomic Signatures for Disease Sub-classification and Target Prioritization in AMP-ADU01AG061359 · NIA · DUKE UNIVERSITY · PI KADDURAH-DAOUK, RIMA F, KASTENMULLER, GABI · 2018 to 2022
$10.0MMechanisms of Brain Dysmorphology in MN1 C-Terminal Truncation Syndrome, a Novel Intellectual Developmental Disability Disorder P50HD103524 · NICHD · UNIVERSITY OF WASHINGTON · PI DANIEL DOHERTY · 2020 to 2026
$9.9MAlzheimer variants: Propagation of shared functional changes across cellular networksU01AG072572 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI DE JAGER, PHILIP L, ST GEORGE-HYSLOP, PETER HENRY · 2021 to 2025
$8.5MProbing Heterogeneity of Alzheimer's Disease Using iPSCsR01AG055909 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI Tracy L YOUNG-PEARSE · 2018 to 2026
$5.7MCell and Molecular Consequences of Alzheimer's Disease Genetic Variants on BBB Integrity and FunctionRF1NS117446 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI YOUNG-PEARSE, TRACY L · 2020 to 2020
$3.6MIdentifying cell type-specific autonomous and non-autonomous interactions in ADRF1AG072167 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI MENON, VILAS, YOUNG-PEARSE, TRACY L · 2022 to 2022
$2.6MBuilding Novel Predictive Networks for high-throughput, in-silico Key Driver Prioritization to Enhance Drug Target Discovery in AMP-AD and M2OVE-ADRF1AG057457 · NIA · UNIVERSITY OF ARIZONA · PI BRADSHAW, ELIZABETH M, CHANG, RUI · 2017 to 2019
$2.3MAnalyses of AD relevant phenotypes in neural cells derived from human iPSCsRF1AG042776 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI YOUNG-PEARSE, TRACY L · 2012 to 2012
$485kElucidating the role of SORL1 as an APOE receptor in human astrocytesF31AG063399 · NIA · HARVARD MEDICAL SCHOOL · PI LEE, HYO · 2020 to 2021
$78kNIA NIH HHS F31 AG063399NIA NIH HHS R01 AG055909NIA NIH HHS RF1 AG042776NIA NIH HHS RF1 AG057457NIA NIH HHS RF1 AG072167NIA NIH HHS U01 AG061356NIA NIH HHS U01 AG061359NIA NIH HHS U01 AG072572NIA NIH HHS U24 AG021886NICHD NIH HHS P50 HD103524NINDS NIH HHS RF1 NS117446
Abstract
SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate the roles of SORL1 in human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in apolipoprotein E (APOE) and clusterin (CLU) and altered lipid profiles. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in postmortem brain. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1-null neurons but does not rescue APOE levels. Pathway analyses implicate transforming growth factor β (TGF-β)/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Taken together, these data provide a mechanistic link between strong genetic risk factors for AD.
Indexed as
Alzheimer DiseaseClusterinApolipoproteins ECell Growth ProcessesHumansLDL-Receptor Related ProteinsMembrane Transport ProteinsNeuronsApolipoproteins ECLU protein, humanClusterinLDL-Receptor Related ProteinsMembrane Transport ProteinsSORL1 protein, humanAlzheimer'samyloidAPOECLUCP: NeuroscienceendolysosomalretromerSMADSORL1tauTGFbeta
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