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

Xue Wang,Minerva M Carrasquillo,Yuhao Min,Özkan İş,Melissa E Murray,Yan W Asmann,Nathan D Price,Steven G Younkin,Thuy Nguyen,Charlotte C.G Ho,Nilüfer Ertekin-Taner,Todd E Golde,Nicholas T Seyfried,Mariet Allen,Dennis W Dickson,Frederick Q Tutor-New,Monica Castanedes Casey,Joseph S Reddy,Cory C Funk ,Stephanie R Oatman ,Aĺlan I Levey ,Kimberly Malphrus

doi:10.1172/jci149904

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.

Highlights

Neurodegenerative proteinopathies such as Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are characterized by aggregation and accumulation of self-proteins within insoluble aggregates[1]
Transcriptomic changes are conserved between AD and PSP
We compared the change in gene expression between AD and control and PSP and control in the temporal cortex (TCx) and cerebellar cortex (CER)(5, 7)

Summary

Introduction

Neurodegenerative proteinopathies such as Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are characterized by aggregation and accumulation of self-proteins within insoluble aggregates[1]. Tau accumulates as NFTs in neurons, as “tufts” in astrocytes (the descriptor “tufted astrocytes”), and in coiled bodies or glial inclusions in oligodendrocytes[3]. In both diseases, numerous lines of research show a strong link between protein aggregation, accumulation and degeneration, though precise mechanism of cellular dysfunction and death remain enigmatic. There is little consensus as to the mechanisms underlying cell dysfunction and death in AD, PSP and other neurodegenerative proteinopathies. Because of this incomplete understanding multiple studies are using system level omics approaches to try and further understand the pathological cascades in AD, PSP and other neurodegenerative proteinopathies[4,5,6]. We compare the transcriptomic changes in two brain regions from a large series of postmortem AD, PSP and control brains

Results and Discussion

Discussion

Figures and figure legends