Biology subjects

Rivera, A. D.

Publications and source records attributed to Rivera, A. D..

2 recordsLinked to original sources

bioRxiv2020

Functional genomic analyses highlights a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells (OPC) and underlying myelin dysregulation in the aged forebrain

Brain aging is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to aging as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain aging hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrates that oligodendroglial and myelin genes are amongst the most altered in the aging mouse cortex. This was underscored by the identification of causal links between signaling pathways and their downstream transcriptional networks that define oligodendroglial disruption in aging. The results highlighted that the G-protein coupled receptor GPR17 is central to the disruption of OPC in aging and this was confirmed by genetic fate mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPC and restore myelination in age-related neuropathological contexts.

neuroscience↗

bioRxiv2020

Accelerated dystrophy and decay of oligodendrocyte precursor cells in the APP/PS1 model of Alzheimer's-like pathology

Myelin disruption is a feature of natural aging and of Alzheimers disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Here, we examined age-related changes in OPCs in APP/PS1 mice, a model for AD-like pathology, compared with non-transgenic (Tg) age-matched controls. Analysis was performed in the CA1 area of the hippocampus following immunolabelling for NG2 with the nuclear dye Hoescht, to identify OPC and OPC sister cells, a measure of OPC replication, together with Gpr17 and Olig2 for oligodendrocytes and myelin basic protein (MBP) immunostaining as a measure of myelination. The results indicate a decrease in the number of OPCs between 9 and 14 months in natural ageing and this occurred earlier at 9 months in APP/PS1 mice, without further decline at 14 months. The number of OPC sister cells was unaltered in natural aging, but declined significantly at 14-months in APP/PS1 mice. The number of GPR17+ and Olig2+ oligodendrocytes was not altered in APP/PS1, whereas MBP immunostaining increased between 9 and 14 months in natural ageing, but not in APP/PS1 mice. Notably, OPCs displayed marked morphological changes at 14 months in APP/PS1 mice, characterized by an overall shrinkage of OPC process domains and increased process branching, characteristic of reactive pathological changes. The results indicate that OPC and myelin disruption are pathological signs in the APP/PS1 mouse model of AD.

neuroscience↗