Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins

Abstract

Cognitive aging is one of the major problems worldwide, especially as people get older. This study aimed to perform global gene expression profiling of cognitive function to identify associated genes and pathways and a novel transcriptional regulatory network analysis to identify important regulons. We performed single transcript analysis on 400 monozygotic twins using an assumption-free generalized correlation coefficient (GCC), linear mixed-effect model (LME) and kinship model and identified six probes (one significant at the standard FDR < 0.05 while the other results were suggestive with 0.18 ≤ FDR ≤ 0.28). We combined the GCC and linear model results to cover diverse patterns of relationships, and meaningful and novel genes like APOBEC3G, H6PD, SLC45A1, GRIN3B, and PDE4D were detected. Our exploratory study showed the downregulation of all these genes with increasing cognitive function or vice versa except the SLC45A1 gene, which was upregulated with increasing cognitive function. Linear models found only H6PD and SLC45A1, the other genes were captured by GCC. Significant functional pathways (FDR < 3.95e-10) such as focal adhesion, ribosome, cysteine and methionine metabolism, Huntington's disease, eukaryotic translation elongation, nervous system development, influenza infection, metabolism of RNA, and cell cycle were identified. A total of five regulons (FDR< 1.3e-4) were enriched in a transcriptional regulatory analysis in which CTCF and REST were activated and SP3, SRF, and XBP1 were repressed regulons. The genome-wide transcription analysis using both assumption-free GCC and linear models identified important genes and biological pathways implicated in cognitive performance, cognitive aging, and neurological diseases. Also, the regulatory network analysis revealed significant activated and repressed regulons on cognitive function.

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis

“…On the contrary, the PDE4D-sparing PDE4 inhibitor ABI-4 did not affect inflammatory processes in murine microglia cultures, excluding a direct role for PDE4D in inflammation (Hedde et al, 2017). Alternatively, PDE4D-specific inhibition has been largely related to improved memory and neuroplasticity (Mohammadnejad et al, 2021;Xiang et al, 2020;Zhang et al, 2017;Shi et al, 2021;Zhang et al, 2014;Sierksma et al, 2014;Cui et al, 2019). However, despite being a therapeutic target, it is hypothesized that especially PDE4D is responsible for the emetic side effects upon pan PDE4 inhibition since PDE4D is highly expressed in the area postrema, the chemoreceptor trigger zone for emesis in the brainstem, compared to other PDE4 genes (Mori et al, 2010).…”

Identifying Genetic Variants Regulating MGMT Gene Expression- A Study in Monozygotic Danish Twins

“…Samples were labeled with Cy5, and the reference consisting of a pool of 16 samples was labeled with Cy3. Hybridization, washing, scanning, and quantification were performed according to the array manufacturer's recommendations [20,21].…”

Ablation of specific long PDE4D isoforms increases neurite elongation and conveys protection against amyloid-β pathology

“…The PDE4D subtype has shown to be a promising target for memory enhancement. In a recent exploratory study, PDE4D expression in blood was found to negatively correlate with cognitive function in monozygotic twins [ 15 ]. Moreover, PDE4D gene variants affect functional brain networks in patients with mild cognitive impairment and AD [ 16 ].…”