Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1
Summary: 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 SO...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723010057 |
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| author | Hyo Lee Aimee J. Aylward Richard V. Pearse, II Alexandra M. Lish Yi-Chen Hsieh Zachary M. Augur Courtney R. Benoit Vicky Chou Allison Knupp Cheryl Pan Srilakshmi Goberdhan Duc M. Duong Nicholas T. Seyfried David A. Bennett Mariko F. Taga Kevin Huynh Matthias Arnold Peter J. Meikle Philip L. De Jager Vilas Menon Jessica E. Young Tracy L. Young-Pearse |
| author_facet | Hyo Lee Aimee J. Aylward Richard V. Pearse, II Alexandra M. Lish Yi-Chen Hsieh Zachary M. Augur Courtney R. Benoit Vicky Chou Allison Knupp Cheryl Pan Srilakshmi Goberdhan Duc M. Duong Nicholas T. Seyfried David A. Bennett Mariko F. Taga Kevin Huynh Matthias Arnold Peter J. Meikle Philip L. De Jager Vilas Menon Jessica E. Young Tracy L. Young-Pearse |
| author_sort | Hyo Lee |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-12T11:53:51Z |
| format | Article |
| id | doaj.art-911ab12d4ed045b69c2a0c7474867a7a |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T11:53:51Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-911ab12d4ed045b69c2a0c7474867a7a2023-08-31T05:02:28ZengElsevierCell Reports2211-12472023-08-01428112994Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1Hyo Lee0Aimee J. Aylward1Richard V. Pearse, II2Alexandra M. Lish3Yi-Chen Hsieh4Zachary M. Augur5Courtney R. Benoit6Vicky Chou7Allison Knupp8Cheryl Pan9Srilakshmi Goberdhan10Duc M. Duong11Nicholas T. Seyfried12David A. Bennett13Mariko F. Taga14Kevin Huynh15Matthias Arnold16Peter J. Meikle17Philip L. De Jager18Vilas Menon19Jessica E. Young20Tracy L. Young-Pearse21Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USADepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USADepartment of Biochemistry, Emory School of Medicine, Atlanta, GA, USADepartment of Biochemistry, Emory School of Medicine, Atlanta, GA, USARush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USACenter 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, USABaker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, AustraliaInstitute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USABaker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, AustraliaCenter 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, USACenter 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, USADepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723010057CP: Neuroscience |
| spellingShingle | Hyo Lee Aimee J. Aylward Richard V. Pearse, II Alexandra M. Lish Yi-Chen Hsieh Zachary M. Augur Courtney R. Benoit Vicky Chou Allison Knupp Cheryl Pan Srilakshmi Goberdhan Duc M. Duong Nicholas T. Seyfried David A. Bennett Mariko F. Taga Kevin Huynh Matthias Arnold Peter J. Meikle Philip L. De Jager Vilas Menon Jessica E. Young Tracy L. Young-Pearse Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1 Cell Reports CP: Neuroscience |
| title | Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1 |
| title_full | Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1 |
| title_fullStr | Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1 |
| title_full_unstemmed | Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1 |
| title_short | Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1 |
| title_sort | cell type specific regulation of apoe and clu levels in human neurons by the alzheimer s disease risk gene sorl1 |
| topic | CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723010057 |
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