Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Jose A Santiago,Virginie Bottero,Judith A Potashkin

doi:10.3390/ijms21062050

Abstract

Background: Dementia is a growing public health concern with an estimated prevalence of 50 million people worldwide. Alzheimer’s disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. Methods: In this study, we compared the transcriptome from the frontal cortex of patients with AD, VaD, and FTD to identify dysregulated pathways. Results: Upregulated genes in AD were enriched in adherens and tight junctions, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase and protein kinase B/Akt signaling pathways, whereas downregulated genes associated with calcium signaling. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Upregulated genes in FTD were associated with ECM receptor interactions and the lysosome, whereas downregulated genes were involved in glutamatergic synapse and MAPK signaling. The transcription factor KFL4 was shared among the 3 types of dementia. Conclusions: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias.

Highlights

Dementia is a major cause of disability and dependency in the elderly with a paramount social and economic impact
Correlation analyses showed that gene expression profiles of subjects with Alzheimer’s disease (AD) significantly overlapped and positively correlated with those affected by vascular dementia (VaD) and frontotemporal dementia (FTD) suggesting that similar molecular changes occur in the frontal cortex of these dementia types
In addition to aquaporin 1 (AQP1), we identified another 11 upregulated genes shared between AD, VaD, and FTD that have been associated with neurodegeneration

Summary

Introduction

Dementia is a major cause of disability and dependency in the elderly with a paramount social and economic impact. The most prevalent cause of dementia is Alzheimer’s disease (AD) [2]. Other types of dementia including vascular dementia (VaD) and frontotemporal dementia (FTD), for example, frequently occur and share many clinical and pathological features making the diagnosis difficult. Alzheimer’s disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Conclusions: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias

Methods

Discussion

Conclusion