Single-nucleus RNA Sequencing Demonstrates an Autosomal Dominant Alzheimer's Disease Profile and Possible Mechanisms of Disease Protection

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2024 Feb 28

PMID 38417436

Authors

Maria Camila Almeida

Sarah J Eger

Caroline He

Morgane Audouard

Arina Nikitina

Stella M K Glasauer

Dasol Han

Barbara Mejia-Cupajita

Juliana Acosta-Uribe

Nelson David Villalba-Moreno

Jessica Lisa Littau

Megan Elcheikhali

Erica Keane Rivera

Daniel Carneiro Carrettiero

Carlos Andres Villegas-Lanau

Diego Sepulveda-Falla

Francisco Lopera

Kenneth S Kosik

Affiliations

Soon will be listed here.

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.

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