Redefining transcriptional regulation of the APOE gene and its association with Alzheimer’s disease

Abstract

The apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet the expression of APOE is not clearly understood. For example, it is unclear whether AD patients have elevated or decreased APOE expression or why the correlation levels of APOE RNA and the ApoE protein differ across studies. Likewise, APOE has a single CpG island (CGI) that overlaps with its 3'-exon, and this CGI's effect is unknown. We previously reported that the APOE CGI is highly methylated in human postmortem brain (PMB) and that this methylation is altered in AD frontal lobe. In this study, we comprehensively characterized APOE RNA transcripts and correlated levels of RNA expression with DNA methylation levels across the APOE CGI. We discovered the presence of APOE circular RNA (circRNA) and found that circRNA and full-length mRNA each constitute approximately one third of the total APOE RNA, with truncated mRNAs likely constituting some of the missing fraction. All APOE RNA species demonstrated significantly higher expression in AD frontal lobe than in control frontal lobe. Furthermore, we observed a negative correlation between the levels of total APOE RNA and DNA methylation at the APOE CGI in the frontal lobe. When stratified by disease status, this correlation was strengthened in controls but not in AD. Our findings suggest a possible modified mechanism of gene action for APOE in AD that involves not only the protein isoforms but also an epigenetically regulated transcriptional program driven by DNA methylation in the APOE CGI.

The APOE gene cluster responds to air pollution factors in mice with coordinated expression of genes that differs by age in humans

“…After age 80, AD brains only had lower expression in NECTIN2 and CLPTM1. These findings confirm associations of elevated APOE mRNA in AD brains,41,42 but indicate a need for a more detailed analysis of brain regions by age.…”

Epigenetics of Alzheimer’s Disease

“…DNA methylation of several specific genes has been investigated using candidate gene approach, with APOE being the most commonly studied gene. So far, inconsistent data have been reported, with DNA methylation being decreased in AD [ 39 , 40 , 41 , 42 ], while some studies found no differences in DNA methylation levels [ 43 , 44 ]. Additional genes of interest have been studied as well, including genes coding for brain-derived neurotrophic factor ( BDNF ) [ 45 ], glycogen synthase kinase 3 beta ( GSK3β) [ 46 ], triggering receptor expressed on myeloid cells 2 ( TREM2 ) [ 47 ], and ankyrin 1 ( ANK1 ) [ 48 ].…”

TOMM40 RNA Transcription in Alzheimer’s Disease Brain and Its Implication in Mitochondrial Dysfunction

“…Increased TOMM40 RNA transcription in AD brains could be a consequence of prolonged mitochondrial dysfunction, which triggers a feedback response to upregulate structural proteins (e.g., TOM40) to compensate for the compromised mitochondrial function. The upregulated TOMM40 RNA in AD brains has the same trend as the upregulation of APOE mRNA in AD brains compared to control [40]. The consistent upregulation of both TOMM40 and APOE in AD brains makes the concept of co-regulation of these genes through the same topological associating domain even more appealing.…”

“…RT-qPCR assays were performed as previously reported [40]. Briefly, a fixed reversetranscribed cDNA input (5 ng) was amplified using TaqMan assays or SYBR PCR assays in a QuantStudio 5 (Applied Biosystems, Thermo Fisher).…”