Langley, Monica R.

Abstract Astrocytes, the most abundant glial cells in the central nervous system (CNS), play essential roles in maintaining neuronal homeostasis, synaptic regulation, and blood–brain barrier integrity. However, these cells can undergo senescence—a cellular state characterized by irreversible growth arrest and the secretion of proinflammatory factors—in response to aging and pathological stressors, contributing to synaptic dysfunction and neurodegenerative diseases. This review examines the molecular mechanisms driving astrocytic senescence, including oxidative stress, DNA damage, and inflammatory signaling pathways such as NF-κB and the senescence-associated secretory phenotype. A particular focus is placed on the diverse array of known chemical inducers of astrocyte senescence, such as pesticides and heavy metals, which provide critical insights into the processes governing cellular aging in the brain. By analyzing the effects of these inducers, we highlight their implications for neurodegenerative disease progression and brain aging. Understanding astrocytic senescence offers new insights into age-related neuropathology and presents promising avenues for targeted therapies in neurodegenerative disorders induced by environmental toxicants.

The cardinal signs of systemic metabolic dysfunction, including insulin resistance, hypertension and a systemic pro‐inflammatory state are risk factors for the development of cardiovascular disease, type 2 diabetes, and neurodegenerative conditions, but there is limited information regarding the impact on recovery after spinal cord injury (SCI). To address this gap, we investigated the impact of systemic insulin resistance generated by consumption of a diet high in fat and sucrose, often referred to as a Western Diet, on neuropathophysiological outcomes in a murine compression model of incomplete SCI. Ten‐week‐old female C57BL6 mice were provided a regular diet (RD) or a diet high in fat and sucrose (HFHS) for 7 weeks prior to experimental compression SCI. Mice consuming a Western Diet showed signs of systemic insulin resistance such as evaluated blood glucose. In addition, signs of insulin resistance within the substance of the spinal cord were also observed, including reductions in the abundance of insulin‐like growth factor 1 receptor (IGF‐1R). Impairments in motor recovery evaluated by BMS score and subscore were present in mice consuming HFHS at 14 and 30 days post injury (dpi). Consumption of a diet rich in fat and sucrose also impaired the mean maximal angle achieved on the inclined plane test and resulted in significant impairments in bladder release. Immunochemical analysis of the spinal cord revealed a number of differences in markers of neural injury between the two groups. First, mice consuming HFHS exhibited significant increases in astrogliosis measured by glial fibrillary acidic protein (GFAP) prior to injury, compared to mice consuming a RD. In fact, the prominent increases in GFAP observed in the intact spinal cord of mice consuming HFHS were equivalent to those observed after SCI in mice consuming a regular chow. In the subacute period, markers of microglial/monocyte activation were elevated in all mice with SCI; however, the increase was substantially greater in the spinal cords of mice consuming HFHS. The spinal cord white matter of mice consuming HFHS also showed reductions in the number of oligodendrocyte progenitor and mature myelinating cells prior to SCI and HFHS‐associated reductions in myelin producing cells persisted at 14 and 30 dpi. In addition, loss of serotonergic axons in the spinal cord after SCI was exacerbated in mice consuming HFHS. Growth associated protein 43 (GAP43), a marker of axonal growth cones was elevated after SCI in the spinal cords of mice consuming a RD or a HFHS diet; however, the magnitude of the increase in growth cones was severely impaired in mice consuming HFHS. These findings suggest that consumption of a Western Diet increases the risk of insulin resistance within the central nervous system and impairs neurobehavioral recovery after SCI. These studies highlight insulin resistance as a new mechanism that limits nervous system repair after SCI and as a potential target for intervention to improve functional outcomes. Support or Funding Information NIH R01 NS052741 and The Minnesota State SCI and TBI Research Grant Program. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

We recently demonstrated that high dietary fat (HFD) consumption results in a dramatic loss of myelinating cells and their progenitors in the adult CNS (Yoon et al., 2016). However, the mechanism(s) by which HFD drives dysmyelination are unknown. Since epidemiological studies indicate that metabolic syndrome is a key risk factor for multiple sclerosis (MS), a better understanding of how HFD contributes to oligodendrocyte loss and the capacity for myelin regeneration has the potential to highlight new treatment targets. In mice fed HFD, we found significant decreases in vertical activity by 4 wk and significant changes in ambulatory and stereotypy movements by 12 wk in the Open Field Test. HFD‐fed mice also spent less time in the center of the field as opposed to the perimeter, indicating an anxious phenotype. Mitochondrial isolated from the spinal cord of mice consuming HFD for 4 wk had significantly higher state 3 and state 4 respiration as determined by high‐resolution respirometry. However, by 12 wk, state 4 mitochondrial respiration was significantly less in the HFD group. Targeted LC‐LC‐mass spectroscopy approaches demonstrated that Citric Acid Cycle intermediates are also depleted in the spinal cord of mice consuming HFD for 12 wk compared to controls. Changes in genes related to mitochondrial morphology, quality control processes, and oxidative stress response were also found. In addition, there were significantly fewer Olig2+ cells and increased signs of lipid peroxidation products (4‐Hydroxynonenal‐immunoreactivity) in the corpus callosum of HFD consuming mice compared to those fed a regular diet. Supporting in vivo findings that oligodendrocytes are reduced in the spinal cord of mice consuming HFD, we observed increased mitochondrial fragmentation and a reduced oxygen consumption rate in oligodendrocyte precursors cultured with palmitic acid. Astrocytes however, significantly increased oxygen consumption following exposure to palmitic acid. Together, these findings suggest that changes in the adult spinal cord in response to HFD consumption creates an environment that is less conducive to neural repair by impacting mitochondria function and morphology and impairing oligodendrocyte function. To determine any impact of HFD on myelin regeneration, studies are ongoing to examine myelin regeneration using a murine model of Cuprizone‐mediated demyelination. Neurobehavioral assessments to date reveal significant interactions between HFD and myelin injury and repair. Understanding the cellular environment in response to dietary factors such as HFD consumption can help to guide care for individuals with MS and other conditions in which myelin loss plays a pathological role and has potential to identify new targets for intervention. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .