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

Maria Camila Almeida; Sarah J Eger; Caroline He; Morgane Audouard; Arina Nikitina; Stella M K Glasauer; Dasol Han; Barbara Mejía-Cupajita; Juliana Acosta-Uribe; Nelson David Villalba-Moreno; Jessica Lisa Littau; Megan Elcheikhali; Erica Keane Rivera; Daniel Carneiro Carrettiero; Carlos Andrés Villegas-Lanau; Diego Sepulveda-Falla; Francisco Lopera; Kenneth S Kosik

doi:10.1016/j.neuron.2024.02.009

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

Neuron. 2024 Feb 21:S0896-6273(24)00093-X. doi: 10.1016/j.neuron.2024.02.009. Online ahead of print.

Authors

Maria Camila Almeida¹, Sarah J Eger², Caroline He², Morgane Audouard², Arina Nikitina², Stella M K Glasauer², Dasol Han², Barbara Mejía-Cupajita³, Juliana Acosta-Uribe³, Nelson David Villalba-Moreno⁴, Jessica Lisa Littau⁴, Megan Elcheikhali⁵, Erica Keane Rivera², Daniel Carneiro Carrettiero¹, Carlos Andrés Villegas-Lanau⁶, Diego Sepulveda-Falla⁴, Francisco Lopera⁷, Kenneth S Kosik⁸

Affiliations

¹ 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.
² Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
³ 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.
⁴ Molecular Neuropathology of Alzheimer's Disease, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁵ Department of Statistics and Applied Probability, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
⁶ Grupo de Neurociencias de Antioquia, School of Medicine, Universidad de Antioquia, Medellín 050010, Colombia.
⁷ Grupo de Neurociencias de Antioquia, School of Medicine, Universidad de Antioquia, Medellín 050010, Colombia. Electronic address: francisco.lopera@gna.org.co.
⁸ 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.

PMID: 38417436
DOI: 10.1016/j.neuron.2024.02.009

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.

Keywords: APOE3 Christchurch; PSEN1-E280A; autophagy; chaperones; single-nucleus sequencing; spatial transcriptomics; sporadic Alzheimer's disease; transcriptomics.