Single-nucleus RNA sequencing demonstrates an autosomal dominant Alzheimer's disease profile and possible mechanisms of disease protection.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 8809320 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4199 (Electronic) Linking ISSN: 08966273 NLM ISO Abbreviation: Neuron Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Cambridge, Mass. : Cell Press, c1988-
    • Subject Terms:
      Alzheimer Disease*/genetics ; Alzheimer Disease*/metabolism ; Alzheimer Disease*/pathology ; Presenilin-1*/genetics; Humans ; Male ; Female ; Low Density Lipoprotein Receptor-Related Protein-1/genetics ; Sequence Analysis, RNA/methods ; Autophagy/genetics ; Transcriptome ; Aged ; Neurons/metabolism ; Neurons/pathology ; Middle Aged ; Astrocytes/metabolism ; Astrocytes/pathology ; Brain/metabolism ; Brain/pathology ; Tacrolimus Binding Proteins/genetics ; Aged, 80 and over ; Single-Cell Analysis
    • Abstract:
      Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials.
      Competing Interests: Declaration of interests K.S.K. consults for ADRx and Expansion Therapeutics and is a member of the Tau Consortium board of directors. F.L. consults for Biogen and Viewmind and has grants from the NIH, Red-Lat, Alzheimer’s Association, Biogen, DIAN-TU, DIAN-Obs, Large PD, and Enroll-HD. J.A.-U .is a consultant for the pharmaceutical company Tecnoquimicas (Colombia).
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • References:
      Nat Neurosci. 2021 Feb;24(2):276-287. (PMID: 33432193)
      Database (Oxford). 2019 Jan 1;2019:. (PMID: 30951143)
      Annu Rev Biochem. 2015;84:435-64. (PMID: 25784053)
      Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
      Biochim Biophys Acta. 2013 Dec;1828(12):2886-97. (PMID: 24099007)
      Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):7285-90. (PMID: 26060301)
      J Clin Lipidol. 2017 Jan - Feb;11(1):12-23.e1. (PMID: 28391878)
      Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2658-63. (PMID: 20133804)
      Protein Eng Des Sel. 2013 Sep;26(9):539-46. (PMID: 23832849)
      Cells. 2019 Mar 01;8(3):. (PMID: 30823664)
      Arch Neurol. 2005 Dec;62(12):1808. (PMID: 16344337)
      Sci Rep. 2018 Jun 11;8(1):8868. (PMID: 29892006)
      PLoS One. 2020 May 21;15(5):e0221669. (PMID: 32437347)
      Commun Biol. 2021 May 26;4(1):629. (PMID: 34040149)
      Nucleic Acids Res. 2022 Jul 5;50(W1):W216-W221. (PMID: 35325185)
      Nat Commun. 2021 Feb 2;12(1):738. (PMID: 33531494)
      Genome Med. 2022 Mar 8;14(1):27. (PMID: 35260199)
      J Biol Chem. 2006 Sep 15;281(37):27633-42. (PMID: 16844686)
      Acta Neuropathol. 2022 Sep;144(3):589-601. (PMID: 35838824)
      J Neurosci. 2014 Sep 3;34(36):11929-47. (PMID: 25186741)
      Brain. 2015 Aug;138(Pt 8):2383-98. (PMID: 26141492)
      Lancet Neurol. 2016 Dec;15(13):1326-1335. (PMID: 27777022)
      J Neurosci Res. 2002 Nov 1;70(3):367-72. (PMID: 12391599)
      Nat Med. 2020 Jan;26(1):131-142. (PMID: 31932797)
      Nature. 2017 Sep 28;549(7673):523-527. (PMID: 28959956)
      Mamm Genome. 2021 Apr;32(2):94-103. (PMID: 33713180)
      Am J Pathol. 1998 Nov;153(5):1365-70. (PMID: 9811326)
      Nature. 2019 Jun;570(7761):332-337. (PMID: 31042697)
      J Neurosci. 2010 Jan 13;30(2):591-9. (PMID: 20071522)
      Neurology. 2014 Jul 15;83(3):253-60. (PMID: 24928124)
      Cell. 2021 May 13;184(10):2696-2714.e25. (PMID: 33891876)
      Nat Neurosci. 2019 Dec;22(12):2087-2097. (PMID: 31768052)
      Neuron. 2021 May 19;109(10):1657-1674.e7. (PMID: 33831349)
      Neuron. 2022 Sep 21;110(18):2929-2948.e8. (PMID: 35882228)
      Cell. 2024 Jan 18;187(2):428-445.e20. (PMID: 38086389)
      Nat Neurosci. 2023 Dec;26(12):2104-2121. (PMID: 37957317)
      Cell. 2023 Sep 28;186(20):4438-4453.e23. (PMID: 37774681)
      Science. 2008 Feb 15;319(5865):916-9. (PMID: 18276881)
      Nat Commun. 2023 Apr 21;14(1):2314. (PMID: 37085492)
      Cell. 2023 Sep 28;186(20):4365-4385.e27. (PMID: 37774677)
      Nat Rev Neurosci. 2009 May;10(5):333-44. (PMID: 19339974)
      Nat Med. 2019 Nov;25(11):1680-1683. (PMID: 31686034)
      Nat Genet. 2021 Aug;53(8):1143-1155. (PMID: 34239132)
      BMC Bioinformatics. 2017 Mar 2;18(1):142. (PMID: 28249561)
      Arch Neurol. 2006 Mar;63(3):370-6. (PMID: 16533963)
      J Alzheimers Dis. 2021;79(1):389-400. (PMID: 33285640)
      Sci Transl Med. 2022 Nov 16;14(671):eabl7646. (PMID: 36383681)
      Acta Neuropathol. 2006 Oct;112(4):389-404. (PMID: 16906426)
      Alzheimers Dement. 2018 Feb;14(2):205-214. (PMID: 28943286)
      J Neurochem. 2010 Dec;115(5):1077-89. (PMID: 20854368)
      Nat Methods. 2017 Oct;14(10):955-958. (PMID: 28846088)
      Brain. 2021 Apr 12;144(3):953-962. (PMID: 33449993)
      Nat Neurosci. 2021 Mar;24(3):425-436. (PMID: 33558695)
      Cell Syst. 2019 Apr 24;8(4):329-337.e4. (PMID: 30954475)
      J Neuropathol Exp Neurol. 2016 Mar;75(3):284-90. (PMID: 26888304)
      Nat Commun. 2020 Nov 30;11(1):6129. (PMID: 33257666)
      Expert Rev Neurother. 2014 Jun;14(6):621-30. (PMID: 24852227)
      Lancet Neurol. 2011 Mar;10(3):213-20. (PMID: 21296022)
      Cell Rep. 2020 Jun 30;31(13):107843. (PMID: 32610143)
      Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):1023-1029. (PMID: 33274538)
      JAMA. 1997 Mar 12;277(10):793-9. (PMID: 9052708)
      Science. 2010 Dec 24;330(6012):1774. (PMID: 21148344)
      Nat Commun. 2019 Apr 3;10(1):1523. (PMID: 30944313)
      Nat Commun. 2021 Sep 28;12(1):5692. (PMID: 34584091)
      Glia. 2010 Aug;58(10):1186-96. (PMID: 20544854)
      Nature. 2020 Apr;580(7803):381-385. (PMID: 32296178)
      J Clin Invest. 2013 Oct;123(10):4158-69. (PMID: 23999428)
      J Cell Biol. 2011 Nov 28;195(5):765-79. (PMID: 22105352)
    • Grant Information:
      RF1 AG062479 United States AG NIA NIH HHS; S10 OD010786 United States OD NIH HHS
    • Contributed Indexing:
      Keywords: APOE3 Christchurch; PSEN1-E280A; autophagy; chaperones; single-nucleus sequencing; spatial transcriptomics; sporadic Alzheimer's disease; transcriptomics
    • Accession Number:
      0 (Presenilin-1)
      0 (PSEN1 protein, human)
      0 (Low Density Lipoprotein Receptor-Related Protein-1)
      0 (LRP1 protein, human)
      EC 5.2.1.- (Tacrolimus Binding Proteins)
    • Publication Date:
      Date Created: 20240228 Date Completed: 20240606 Latest Revision: 20240613
    • Publication Date:
      20240613
    • Accession Number:
      PMC11156559
    • Accession Number:
      10.1016/j.neuron.2024.02.009
    • Accession Number:
      38417436