Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1.

Humans Clusterin / genetics Alzheimer Disease / genetics Neurons Cell Growth Processes Apolipoproteins E / genetics LDL-Receptor Related Proteins / genetics Membrane Transport Proteins
APOE Alzheimer's CLU CP: Neuroscience SMAD SORL1 TGFbeta amyloid endolysosomal retromer tau

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
29 08 2023
Historique:
received: 19 05 2022
revised: 04 07 2023
accepted: 01 08 2023
medline: 4 9 2023
pubmed: 24 8 2023
entrez: 23 8 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2023.112994 PMID: 37611586 PMC: PMC10568487
pubmed: 37611586
pii: S2211-1247(23)01005-7
doi: 10.1016/j.celrep.2023.112994
pmc: PMC10568487
mid: NIHMS1928291
pii:
doi:

Substances chimiques

Clusterin 0
Apolipoproteins E 0
SORL1 protein, human 0
LDL-Receptor Related Proteins 0
Membrane Transport Proteins 0
CLU protein, human 0

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

112994

Subventions

Organisme : NIA NIH HHS
ID : U01 AG061356
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG055909
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG072572
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG072167
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061359
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS117446
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057457
Pays : United States
Organisme : NIA NIH HHS
ID : F31 AG063399
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG042776
Pays : United States

Commentaires et corrections

Type : UpdateOf

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Hyo Lee (H)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Aimee J Aylward (AJ)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Richard V Pearse (RV)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Alexandra M Lish (AM)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Yi-Chen Hsieh (YC)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Zachary M Augur (ZM)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Courtney R Benoit (CR)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Vicky Chou (V)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Allison Knupp (A)

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.

Cheryl Pan (C)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Srilakshmi Goberdhan (S)

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Duc M Duong (DM)

Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA.

Nicholas T Seyfried (NT)

Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA.

David A Bennett (DA)

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Mariko F Taga (MF)

Center 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 Huynh (K)

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia.

Matthias Arnold (M)

Institute 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 Meikle (PJ)

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia.

Philip L De Jager (PL)

Center 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 Menon (V)

Center 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 Young (JE)

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.

Tracy L Young-Pearse (TL)

Ann 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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Cell-type-specific regulation of APOE and CLU...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Chaperons moléculaires › Clusterine › Cell-type-specific regulation of APOE and CLU...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Cell-type-specific regulation of APOE and CLU...
questionsmedicales.fr › Cellules › Neurones › Cell-type-specific regulation of APOE and CLU...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Cell-type-specific regulation of APOE and CLU...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Apolipoprotéines E › Cell-type-specific regulation of APOE and CLU...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux lipoprotéines › Récepteurs aux lipoprotéines LDL › Protéines apparentées au récepteur LDL › Cell-type-specific regulation of APOE and CLU...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Cell-type-specific regulation of APOE and CLU...