Frances (Fara) Tolibzoda Zakusilo - PhD Candidate, Advisors: Vera Gorbunova, PhD and Kerry O'Banion, MD/Phd
The role of extracellular components in the aging phenotype is not well understood. A longliving rodent, Naked Mole Rat (NMR), presents as a salient model of healthy aging. Previous findings in our lab have identified extracellular matrix (ECM) component hyaluronic acid (HA) asan important contributor to the exceptional resilience of NMR to aging associated disease, suchas cancer and degenerative conditions. Our lab designed a high-molecular weight HA (HMW-HA)mouse model (nmrHas2;Cre mice) to mimic the major component of NMR ECM. Pilot data indicated that nmrHas2;Cre mice display significant increase in longevity (~5-15%) and resilienceto oncology. We, however, were not able to see a rescue of memory decline, degeneration, andinflammation associated with aging in these transgenic mice. To test the effect of HMW-HA inAlzheimer’s Disease (AD) we generated nmrHas2;Cre x MAPT/P301S double transgenic mice. These mice failed to show reduction in degeneration and inflammation, but as part of this work,we discovered that HA distribution appears to be distorted in AD as compared to healthy adult(10-months-old, 10mo) and aged (~24mo) mice, which points at HA as an intriguing diagnostictool for this neurodegenerative disease.
Since HA is deposited by multiple cells in the brain, we decided to parse apart the effect of thepolymer for a number of cell types. We purified NMR neurons, OPCs, and astroglia and assessedtheir HA profile. OPCs had the least amount of HA, followed by neurons, with astroglia culturemedia having the greatest abundance of HA. We checked if there was a correlation with resilience to stress and discovered that although astroglia were most resilient to reactive oxidative species (ROS), the correlation did not hold for other cells. That made us question therole of HA in ROS stress, one of the major contributors to aging, and look deeper into what mechanisms underly NMR astroglia’s resilience. In addition to NMR, we optimized astroglial cultures from mice and degus, rodents hypothesized to be a natural model for AD developmentwith age, and obtained human fetal astrocytes to perform a comparative study. Interestingly, human cells showed the greatest susceptibility to ROS stress compared to other species, withNMR showing greatest survival among all four. RNA sequencing analysis helped us uncover metabolism related differences between the species, where human astroglia appeared to bemost dependent on glycolysis compared to others. We have been able to significantly increasesurvival post ROS exposure in human cells by subjecting them to ketogenic and reduced nutrient media, which supports the notion of the importance of metabolic state in resilience tooxidative damage. Taken together, this work suggests that there are cell specific mechanisms inthe NMR CNS that allow for their exceptional resilience to the diseases associated with aging.
May 25, 2022 @ 11:00 a.m.
Medical Center | Ryan Case Methods Room (1-9576)
Host: the Neuroscience Graduate Program