Alzheimer's disease and progressive supranuclear palsy share similar transcriptomic changes in distinct brain regions

• Type of Material: Article
• Authors: Xue Wang, Mayo Clinic Florida; Mariet Allen, Mayo Clinic Florida; Özkan İş, Mayo Clinic Florida; Joseph S Reddy, Mayo Clinic Florida; Frederick Q Tutor-New, Mayo Clin Florida; Monica Castanedes Casey, Mayo Clinic Florida; Minerva M Carrasquillo, Mayo Clinic Florida; Stephanie R Oatman, Mayo Clinic Florida; Yuhua Min, Mayo Clinic Florida; Yan W Asmann, Mayo Clinic Florida; Cory Funk, Inst Syst Biol; Thuy Nguyen, Mayo Clinic Florida; Charlotte CG Ho, Mayo Clinic Florida; Kimberly G Malphrus, Mayo Clinic Florida; Nicholas Seyfried, Emory University; Allan Levey, Emory University; Steven G Younkin, Mayo Clinic Florida; Melissa E Murray, Mayo Clinic Florida; Dennis W Dickson, Mayo Clinic Florida; Nathan D Price, Institute for Systems Biology; Todd Golde, Emory University; Nilüfer Ertekin-Taner, Mayo Clinic Florida
• Language: English
• Date: 2022-01-18
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Wang et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI149904
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 132
• Issue: 2
• Keywords: Life Sciences & Biomedicine; Science & Technology; NETWORKS; Medicine, Research & Experimental; Research & Experimental Medicine
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer’s disease (AD), however, neither disease nor brain region specificity of these transcriptome alterations has been explored. Using RNA-Seq data from 231 temporal cortex and 224 cerebellum samples from patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identified a striking correlation in the directionality and magnitude of gene expression changes between these 2 neurodegenerative proteinopathies. Further, the transcriptomic changes in AD and PSP brains ware highly conserved between the temporal and cerebellar cortices, indicating that highly similar transcriptional changes occur in pathologically affected and grossly less affected, albeit functionally connected, areas of the brain. Shared up- or downregulated genes in AD and PSP are enriched in biological pathways. Many of these genes also have concordant protein changes and evidence of epigenetic control. These conserved transcriptomic alterations of 2 distinct proteinopathies in brain regions with and without significant gross neuropathology have broad implications. AD and other neurodegenerative diseases are likely characterized by common disease or compensatory pathways with widespread perturbations in the whole brain. These findings can be leveraged to develop multifaceted therapies and biomarkers that address these common, complex, and ubiquitous molecular alterations in neurodegenerative diseases.