Long noncoding RNAs (lncRNAs) mediate important epigenetic regulation in a wide range of biological processes and diseases. We applied comprehensive analyses of RNA-seq and CAGE-seq (cap analysis of gene expression and sequencing) to characterize the dynamic changes in lncRNA expression in rhesus macaque (Macaca mulatta) brain in four representative age groups. We identified 18 anatomically diverse lncRNA modules and 14 mRNA modules representing spatial, age, and sex specificities. Spatiotemporal-and sex-biased changes in lncRNA expression were generally higher than those observed in mRNA expression. A negative correlation between lncRNA and mRNA expression in cerebral cortex was observed and functionally validated. Our findings offer a fresh insight into spatial-, age-, and sex-biased changes in lncRNA expression in macaque brain and suggest that the changes represent a previously unappreciated regulatory system that potentially contributes to brain development and aging.
The abundance and function of circular RNAs (circRNAs) in mammalian brain have been reported, but their alterations in the biology of brain aging remain elusive. Here, using deep RNA profiling with linear RNA digestion by RNase R we explored a comprehensive map of changes in circRNA expression in rhesus macaque (macaca mulatta) brain in two age groups from adult (10 y) to aged (20 y) periods. Total 17,050 well expressed, stable circRNAs were identified. Cluster analysis reveals that dynamic changes in circRNA expression show the spatial-, sex- and age-biased specificities. On the basis of separate profiling of the RNAs, age-related circRNAs show differential correlation to host mRNA expression. Furthermore, two voltage-dependent L- and R-type calcium channel gene-derived circCACNA2D1 and circCACNA1E negatively regulate their host mRNA expression. Our results demonstrate the power of changes in circRNA expression to reveal insights into a potentially circRNA-mediated regulatory mechanism underlying the biology of brain aging.
Parkinson's disease (PD) is an age-dependent neurodegenerative disease that often occurs in those over age 60. Although rodents and small animals have been used widely to model PD and investigate its pathology, their short life span makes it difficult to assess the aging-related pathology that is likely to occur in PD patient brains. Here, we used brain tissues from rhesus monkeys at 2-3, 7-8, and Ͼ15 years of age to examine the expression of Parkin, PINK1, and ␣-synuclein, which are known to cause PD via loss-or gain-of-function mechanisms. We found that ␣-synuclein is increased in the older monkey brains, whereas Parkin and PINK1 are decreased or remain unchanged. Because of the gain of toxicity of ␣-synuclein, we performed stereotaxic injection of lentiviral vectors expressing mutant ␣-synuclein (A53T) into the substantia nigra of monkeys and found that aging also increases the accumulation of A53T in neurites and its associated neuropathology. A53T also causes more extensive reactive astrocytes and axonal degeneration in monkey brain than in mouse brain. Using monkey brain tissues, we found that A53T interacts with neurofascin, an adhesion molecule involved in axon subcellular targeting and neurite outgrowth. Aged monkey brain tissues show an increased interaction of neurofascin with A53T. Overexpression of A53T causes neuritic toxicity in cultured neuronal cells, which can be attenuated by transfected neurofascin. These findings from nonhuman primate brains reveal age-dependent pathological and molecular changes that could contribute to the age-dependent neuropathology in PD.
Recent studies have demonstrated that formaldehyde (FA)—induced neurotoxicity is important in the pathogenesis of Alzheimer's disease (AD). Elevated levels of FA have been associated with memory impairments and the main hallmarks of AD pathology, including β-amyloid plaques, tau protein hyperphosphorylation, and neuronal loss. Resveratrol (Res), as a polyphenol anti-oxidant, has been considered to have therapeutic potential for the treatment of AD. However, it has not been elucidated whether Res can exert its neuroprotective effects against FA-induced neuronal damages related to AD pathology. To answer this question, the effects of Res were investigated on Neuro-2a (N2a) cells prior to and after FA exposure. The experiments found that pre-treatment with Res significantly decreased FA-induced cytotoxicity, reduced cell apoptosis rates, and inhibited the hyperphosphorylation of tau protein at Thr181 in a dose-dependent manner. Further tests revealed that this effect was associated with the suppression of glycogen synthase kinase (GSK-3β) and calmodulin-dependent protein kinase II (CaMKII) activities, both of which are important kinases for tau protein hyperphosphorylation. In addition, Res was found to increase the activity of phosphoseryl/phosphothreonyl protein phosphatase-2A (PP2A). In summary, these findings provide evidence that Res protects N2a cells from FA-induced damages and suggests that inhibition of GSK-3β and CaMKII and the activation of PP2A by Res protect against the hyperphosphorylation and/or mediates the dephosphorylation of tau protein, respectively. These possible mechanisms underlying the neuroprotective effects of Res against FA-induced damages provide another perspective on AD treatment via inhibition of tau protein hyperhosphorylation.
A recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology has provided a new impetus to investigate the chronic effects of methanol exposure. This paper expands this investigation to the non-human primate, rhesus macaque, through the chronic feeding of young male monkeys with 3% methanol ad libitum. Variable Spatial Delay Response Tasks of the monkeys found that the methanol feeding led to persistent memory decline in the monkeys that lasted 6 months beyond the feeding regimen. This change coincided with increases in tau protein phosphorylation at residues T181 and S396 in cerebrospinal fluid during feeding as well as with increases in tau phosphorylated aggregates and amyloid plaques in four brain regions postmortem: the frontal lobe, parietal lobe, temporal lobe, and the hippocampus. Tau phosphorylation in cerebrospinal fluid was found to be dependent on methanol feeding status, but phosphorylation changes in the brain were found to be persistent 6 months after the methanol feeding stopped. This suggested the methanol feeding caused long-lasting and persistent pathological changes that were related to AD development in the monkey. Most notably, the presence of amyloid plaque formations in the monkeys highlighted a marked difference in animal systems used in AD investigations, suggesting that the innate defenses in mice against methanol toxicity may have limited previous investigations into AD pathology. Nonetheless, these findings support a growing body of evidence that links methanol and its metabolite formaldehyde to AD pathology.
Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Here, we report that circGRIA1, a conserved circRNA isoform derived from the genomic loci of α-mino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit Gria1, shows an age-related and male-specific increase in expression in the rhesus macaque prefrontal cortex and hippocampus. We show circGRIA1 is predominantly localized to the nucleus, and find an age-related increase in its association with the promoter region of Gria1 gene, suggesting it has a regulatory role in Gria1 transcription. In vitro and in vivo manipulation of circGRIA1 negatively regulates Gria1 mRNA and protein levels. Knockdown of circGRIA1 results in an age-related improvement of synaptogenesis, and GluR1 activity-dependent synaptic plasticity in the hippocampal neurons in males. Our findings underscore the importance of circRNA regulation and offer an insight into the biology of brain aging.
FA was found to induce major AD-like pathological markers and cognitive impairments in young rhesus monkeys independent of genetic predispositions. This suggests FA may play a significant role in the initiation and progression of the disease.
Evidence from epidemiological studies has proved that periconceptional use of folic acid (FA) can significantly reduce the risk of neural tube defects (NTDs). However, it is hard to explore when and how FA plays roles in neurogenesis and brain development in vivo, especially in human or other nonhuman primate systems. Primate embryonic stem cell (ESC) lines are ideal models for studying cell differentiation and organogenesis in vitro. In the present study, the roles of FA in neural differentiation were assessed in a rhesus monkey ESC system in vitro. The results showed no significant difference in the expression of neural precursor markers, such as nestin, Sox-1, or Pax-6, among neural progenitors obtained from different FA concentrations or with the FA antagonist methotrexate (MTX). However, FA depletion decreased cell proliferation and affected embryoid body (EB) and neural rosette formation, as well as neuronal but not neuroglia differentiation. Our data imply that the ESC system is a suitable model for further exploring the mechanism of how FA works in prevention of NTDs in primates.
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