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

Autor:	Almeida MC; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Center for Natural and Humans Sciences, Federal University of ABC, Sao Bernardo do Campo, SP 09608020, Brazil., Eger SJ; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., He C; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Audouard M; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Nikitina A; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Glasauer SMK; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Han D; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Mejía-Cupajita B; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Grupo de Neurociencias de Antioquia, School of Medicine, Universidad de Antioquia, Medellín 050010, Colombia., Acosta-Uribe J; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Grupo de Neurociencias de Antioquia, School of Medicine, Universidad de Antioquia, Medellín 050010, Colombia., Villalba-Moreno ND; Molecular Neuropathology of Alzheimer's Disease, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Littau JL; Molecular Neuropathology of Alzheimer's Disease, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Elcheikhali M; Department of Statistics and Applied Probability, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Rivera EK; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Carrettiero DC; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Center for Natural and Humans Sciences, Federal University of ABC, Sao Bernardo do Campo, SP 09608020, Brazil., Villegas-Lanau CA; Grupo de Neurociencias de Antioquia, School of Medicine, Universidad de Antioquia, Medellín 050010, Colombia., Sepulveda-Falla D; Molecular Neuropathology of Alzheimer's Disease, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Lopera F; Grupo de Neurociencias de Antioquia, School of Medicine, Universidad de Antioquia, Medellín 050010, Colombia. Electronic address: francisco.lopera@gna.org.co., Kosik KS; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA. Electronic address: kosik@ucsb.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2024 Jun 05; Vol. 112 (11), pp. 1778-1794.e7. Date of Electronic Publication: 2024 Feb 27.
DOI:	10.1016/j.neuron.2024.02.009
Abstrakt:	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.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu