Temporal Integrative Analysis of mRNA and microRNAs Expression Profiles and Epigenetic Alterations in Female SAMP8, a Model of Age-Related Cognitive Decline

Abstract

A growing body of research shows that epigenetic mechanisms are critically involved in normal and pathological aging. The Senescence-Accelerated Mouse Prone 8 (SAMP8) can be considered a useful tool to better understand the dynamics of the global epigenetic landscape during the aging process since its phenotype is not fully explained by genetic factors. Here we investigated dysfunctional age-related transcriptional profiles and epigenetic programming enzymes in the hippocampus of 2- and 9-month-old SAMP8 female mice using the Senescent-Accelerated Resistant 1 (SAMR1) mouse strain as control. SAMP8 mice presented 1,062 genes dysregulated at 2 months of age, and 1,033 genes at 9 months, with 92 genes concurrently dysregulated at both ages compared to age-matched SAMR1. SAMP8 mice showed a significant decrease in global DNA methylation (5-mC) at 2 months while hydroxymethylation (5-hmC) levels were increased in SAMP8 mice at 2 and 9 months of age compared to SAMR1. These changes were accompanied by changes in the expression of several enzymes that regulate 5-mC and methylcytosine oxidation. Acetylated H3 and H4 histone levels were significantly diminished in SAMP8 mice at 2-month-old compared to SAMR1 and altered Histone DeACetylase (HDACs) profiles were detected in both young and old SAMP8 mice. We analyzed 84 different mouse miRNAs known to be altered in neurological diseases or involved in neuronal development. Compared with SAMR1, SAMP8 mice showed 28 and 17 miRNAs differentially expressed at 2 and 9 months of age, respectively; 6 of these miRNAs overlapped at both ages. We used several bioinformatic approaches to integrate our data in mRNA:miRNA regulatory networks and functional predictions for young and aged animals. In sum, our study reveals interplay between epigenetic mechanisms and gene networks that seems to be relevant for the progression toward a pathological aging and provides several potential markers and therapeutic candidates for Alzheimer's Disease (AD) and age-related cognitive impairment.

Neuroinflammation as a Common Feature of Neurodegenerative Disorders

“…These reports demonstrated that coadministration of these molecules induces a progressive, l-dopa-responsive PD which is preceded by gastric dysmotility (Anselmi et al, 2018). Finally, it is important to notice the role of the microbiota in the CNS, where the host is constantly controlling the maturation and function of the microglial cells (Cosin-Tomas et al, 2018), a reason to consider their effects and imbalances in the subject, which, in the future, could be key in the control, prevention, or even treatment of PD.…”

Epigenetics: Recent Advances and Its Role in the Treatment of Alzheimer's Disease

“…In the 3xTg-AD mouse model, global methylation and hydroxymethylation levels are reduced (87). In the SAMP8 mouse model, global DNA methylation levels are decreased while 5-hmC levels are upregulated (88).…”

MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: Lessons from animal models

“…Thus achieving aging-associated molecular changes of the brain can provide a tool for distinguishing pathological amendments from normal ones. The miRNAs, as a part of epigenetic mechanisms, drastically contribute to cellular senescence, aging, and diseases (Cosín-Tomás et al, 2018).…”

“…Thus achieving aging‐associated molecular changes of the brain can provide a tool for distinguishing pathological amendments from normal ones. The miRNAs, as a part of epigenetic mechanisms, drastically contribute to cellular senescence, aging, and diseases (Cosín‐Tomás et al, 2018). However, only a few miRNAs have been characterized by linking to the age‐related cellular or organic alternations (Luceri et al, 2017).…”