A Regulatory Role for the Insulin- and BDNF-Linked RORA in the Hippocampus: Implications for Alzheimer's Disease

Abstract

Abstract. Alzheimer's disease (AD) is the leading cause of dementia. The etiology of AD remains, in large part, unresolved. In this study, gene expression (microarray) data from postmortem brains in normal aged as well as AD-affected brains in conjunction with transcriptional regulatory networks were explored for etiological insights. The focus was on the hippocampus, a brain region key to memory and learning. The transcriptional regulatory networks were inferred using a trees-based (random forests or extra-trees) as well as a mutual information-based algorithm applied to compendia of adult mouse whole brain and hippocampus microarray data. Network nodes representing human orthologs of the mouse networks were used in the subsequent analysis. Among the potential transcriptional regulators tied to insulin or brain-derived neurotrophic factor (INS1, INS2, BDNF), whose peptide products have been linked to AD, is the Retinoic Acid Receptor-Related Orphan Receptor (RORA). RORA is a nuclear receptor transcription factor whose expression is distinctly upregulated in the AD hippocampus. A notable cross-section of genes differentially expressed in the AD hippocampus was found to be linked to RORA in the networks. Furthermore, several genes associated with RORA in the networks, such as APP, DNM1L, and TIA1 have been implicated in AD. Computationallyderived clusters and modules within the networks indicated strong ties between RORA and genes involved in the AD etiology. In addition, a functional mapping scheme using activity and interaction data affirmed the same network links to RORA. Thus, RORA emerges as a gene with a probable central role in the AD pathology/etiology.

Effects of circadian clock genes and environmental factors on cognitive aging in old adults in a Taiwanese population

“…By using psychometric tests of cognitive function, Ersland et al found that there was a strong association between the RORB gene and a test of verbal intelligence [19]. Consistent with this notion, Acquaah-Mensah et al reported that the expression of the RORA gene is distinctly up-regulated in the hippocampi of AD-affected postmortem human brains, a brain region key to memory and learning, indicating a potential link between RORA and AD [20]. In terms of brain cognitive functions such as mood, the RORA gene was reported to increase the risk of acquiring psychiatric and neurological disorders, including bipolar disorder [6], autism spectrum disorder [21], and post-traumatic stress disorder [22].…”

MiR-18a-downregulated RORA inhibits the proliferation and tumorigenesis of glioma using the TNF-α-mediated NF-κB signaling pathway

“…RORA is reduced in the brain and lymphoblastoid cell lines of multiple cohorts of individuals with autism spectrum disorder [25]. RORA is specifically upregulated in the Alzheimer's disease (AD) hippocampus and emerges as a gene with a probable central role in AD pathology/etiology [24]. Microdeletions overlapping RORA on 15q22.2 can also lead to epileptic seizures and mild intellectual disabilities [38].…”

Phosphoenolpyruvate Carboxykinase, a Key Enzyme That Controls Blood Glucose, Is a Target of Retinoic Acid Receptor-Related Orphan Receptor α

“…In addition, a RORα inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes [ 35 ]. RORα also potentially regulates transcription of brain-derived neurotrophic factor, which is associated with Alzheimer’s disease [ 36 – 38 ]. Finally, IkappaBzeta cooperates with RORα to regulate the development of T helper 17 cells during inflammation [ 39 – 42 ].…”