Key Genes and Biochemical Networks in Various Brain Regions Affected in Alzheimer's Disease.

Morteza Abyadeh,Mafruha Hasan,Paul A Haynes,Saeedeh Hosseinian,Ghasem H Salekdeh,Mehdi Mirzaei,Veer Gupta,Matthew J Fitzhenry,Vivek Gupta,Koorosh Shahpasand,Nitin Chitranshi,Nahid Tofigh,Ardeshir Amirkhani

doi:10.3390/cells11060987

Abstract

Alzheimer’s disease (AD) is one of the most complicated progressive neurodegenerative brain disorders, affecting millions of people around the world. Ageing remains one of the strongest risk factors associated with the disease and the increasing trend of the ageing population globally has significantly increased the pressure on healthcare systems worldwide. The pathogenesis of AD is being extensively investigated, yet several unknown key components remain. Therefore, we aimed to extract new knowledge from existing data. Ten gene expression datasets from different brain regions including the hippocampus, cerebellum, entorhinal, frontal and temporal cortices of 820 AD cases and 626 healthy controls were analyzed using the robust rank aggregation (RRA) method. Our results returned 1713 robust differentially expressed genes (DEGs) between five brain regions of AD cases and healthy controls. Subsequent analysis revealed pathways that were altered in each brain region, of which the GABAergic synapse pathway and the retrograde endocannabinoid signaling pathway were shared between all AD affected brain regions except the cerebellum, which is relatively less sensitive to the effects of AD. Furthermore, we obtained common robust DEGs between these two pathways and predicted three miRNAs as potential candidates targeting these genes; hsa-mir-17-5p, hsa-mir-106a-5p and hsa-mir-373-3p. Three transcription factors (TFs) were also identified as the potential upstream regulators of the robust DEGs; ELK-1, GATA1 and GATA2. Our results provide the foundation for further research investigating the role of these pathways in AD pathogenesis, and potential application of these miRNAs and TFs as therapeutic and diagnostic targets.

Highlights

Alzheimer’s disease (AD) is the leading cause of dementia, affecting between 70 to 80% of older adults with dementia [1]
Repeated failure in clinical trials has challenged our understanding of this multifactorial disease, leading to recent studies concentrating on advancing our knowledge of the underlying mechanisms of AD pathogenesis to find druggable targets
A comprehensive search was performed through the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) datasets to identify eligible data from inception to March 2021

Summary

Introduction

Alzheimer’s disease (AD) is the leading cause of dementia, affecting between 70 to 80% of older adults with dementia [1]. Over 50 million people are living with the disease worldwide, and this number is estimated to rise to 150 million in 2050, exacerbating an already constrained healthcare system unless preventive strategies are implemented [2,3]. There are a growing number of studies focusing on potential therapeutic agents to combat AD more directly [5–7]. Most of these studies are focused on two main pathological hallmarks of AD: senile plaques (SPs) composed of amyloid beta (Aβ) peptides; and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins [3–5,8]. Repeated failure in clinical trials has challenged our understanding of this multifactorial disease, leading to recent studies concentrating on advancing our knowledge of the underlying mechanisms of AD pathogenesis to find druggable targets

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