A Systems View of the Differences between APOE ε4 Carriers and Non-carriers in Alzheimer's Disease.

Shan Jiang,Na Zhao,Wanling Yang,Ling Tang,Yu Qiu,Hong-Zhuan Chen

doi:10.3389/fnagi.2016.00171

Shan Jiang, Na Zhao + Show 4 more

Open Access

https://doi.org/10.3389/fnagi.2016.00171

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Abstract

APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) and accounts for 50–65% of late-onset AD. Late-onset AD patients carrying or not carrying APOE ε4 manifest many clinico-pathological distinctions. Thus, we applied a weighted gene co-expression network analysis to identify specific co-expression modules in AD based on APOE ε4 stratification. Two specific modules were identified in AD APOE ε4 carriers and one module was identified in non-carriers. The hub genes of one module of AD APOE ε4 carriers were ISOC1, ENO3, GDF10, GNB3, XPO4, ACLY and MATN2. The other module of AD APOE ε4 carriers consisted of 10 hub genes including ANO3, ARPP21, HPCA, RASD2, PCP4 and ADORA2A. The module of AD APOE ε4 non-carriers consisted of 16 hub genes including DUSP5, TNFRSF18, ZNF331, DNAJB5 and RIN1. The module of AD APOE ε4 carriers including ISOC1 and ENO3 and the module of non-carriers contained the most highly connected hub gene clusters. mRNA expression of the genes in the cluster of the ISOC1 and ENO3 module of carriers was shown to be correlated in a time-dependent manner under APOE ε4 treatment but not under APOE ε3 treatment. In contrast, mRNA expression of the genes in the cluster of non-carriers’ module was correlated under APOE ε3 treatment but not under APOE ε4 treatment. The modules of carriers demonstrated genetic bases and were mainly enriched in hereditary disorders and neurological diseases, energy metabolism-associated signaling and G protein-coupled receptor-associated pathways. The module including ISOC1 and ENO3 harbored two conserved promoter motifs in its hub gene cluster that could be regulated by common transcription factors and miRNAs. The module of non-carriers was mainly enriched in neurological, immunological and cardiovascular diseases and was correlated with Parkinson’s disease. These data demonstrate that AD in APOE ε4 carriers involves more genetic factors and particular biological processes, whereas AD in APOE ε4 non-carriers shares more common pathways with other types of diseases. The study reveals differential genetic bases and pathogenic and pathological processes between carriers and non-carriers, providing new insight into the mechanisms of the differences between APOE ε4 carriers and non-carriers in AD.

Highlights

Alzheimer’s disease (AD) is one of the leading causes of dementia and is characterized by cognitive decline with distinctive brain pathology such as amyloid plaques and neurofibrillary tangles (Selkoe, 2003)
Transcriptomic data from three brain regions– Brodmann area 9 (BA9) of the prefrontal cortex, the putamen (PT) and the entire substantia nigra (SN) of Parkinson’s Disease (PD) patients were available for analysis
Among the detected PD-specific co-expression modules, only the purple module detected in BA9 of the prefrontal cortex which is the most PD-specific module (Supplementary Figure S5) was significantly correlated with the light cyan module of AD APOE ε4 non-carriers with an extremely low P-value (Figure 7A, P = 9.522 × 10−24, Supplementary Table S26 for detailed overlapped genes)

Summary

Introduction

Alzheimer’s disease (AD) is one of the leading causes of dementia and is characterized by cognitive decline with distinctive brain pathology such as amyloid plaques and neurofibrillary tangles (Selkoe, 2003). Rare familial AD (FAD) is an early onset disease and is caused by several definite and specific genes, such as amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) (Scheuner et al, 1996; Campion et al, 1999). The etiology of the most common form of non-familial late-onset AD appears to be more complicated. Alterations in many molecules and biological processes have been recognized in AD (Mattson, 2004). It seems impractical to uncover the relationships among all of these molecules and biological processes one by one. The exploration of the pathogenic and pathological mechanisms of AD in a systematic view may be more appropriate

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