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Deciphering the molecular mechanisms behind age-related memory loss

Forgetfulness and memory loss can be a normal part of aging, but can also mean the onset of dementia, one of the leading causes of disability and dependency in older people.

With a rapidly aging world population where 1.4 billion people are expected to be over 60 by 2030, understanding age-related memory decline couldn’t be more critical. By deciphering the molecular mechanisms behind our aging, the hope is to prevent age-related memory loss and improve the quality of our lives in later years.

A recent study driven by Professor Ann Massie and his team from the Vrije Universiteit Brussel, published in Molecular Psychiatry, may reveal clues on how to prevent age-related memory loss. Massie and his team have identified that, surprisingly, the loss of a membrane transport protein – the xc- antiporter system – prevents memory loss during aging in mice.


In an interview with Technology networks, Massie tells us about his research and explains why this discovery was unexpected.

Katie Brighton (KB): Can you highlight the importance of studying the physiological aging process?

Ann Massie (AM): Our life expectancy increases sharply; we can’t avoid growing old, but we can try to avoid spending the extra years in poor health. Understanding the physiological aging process will give us clues to understand the pathological aging process.

KB: Can you explain the function of the xc-system, and what we know about this system so far?

A M: The xc- system, with xCT as the specific subunit, is an antiporter that exports cystine in exchange for glutamate. Imported cystine will be reduced to cysteine, which can be used as a building block in the synthesis of glutathione, an important antioxidant.

In the brain, exported glutamate can modulate glutamatergic neurotransmission or, when present in excess, induce toxicity. Improving the xc- system could thus have a double effect: increasing its activity could lead to a better defense system against oxidative stress but could also contribute to the toxicity caused by excess glutamate in the brain. We and others were unable to detect signs of increased oxidative stress in the brains of mice with a genetic deletion of the antiporter. However, we have already identified this antiporter as an important source of extracellular glutamate in several brain regions.1,2 Several lines of evidence have also pointed to a function of the xc- system in driving neuroinflammation.3,4,5 Finally, we have previously reported that genetic loss of the xc- system leads to protective effects in mouse models for seizures, epilepsy, some models for Parkinson’s disease, etc.1,6,2,seven

KB: What key technologies and methodologies have you adopted in this research study, and why?


A M: Given the very broad scope of this study, many technologies were used. To better understand how mice age in the presence and absence of the xc- system, we analyzed lifespan and performed live analyzes on our mice. This includes grip strength measurements, blood tests, glucose tolerance tests, clinical frailty analyzes and even cognitive functions using a specific maze, called the Barnes maze. With the latter, we were able to observe that the cognitive function of mice that age in the absence of the xc – system is preserved, unlike “normal” mice. Since the xc- system is mainly expressed in the central nervous system and on cells of the immune system, we studied the differences in immune cell populations by flow cytometry and measured different markers of inflammation in the blood and in the cells. hippocampus. We investigated the morphology and functionality of hippocampal neurons, using slice microscopy and electrophysiology, respectively. To try to understand the mechanism behind the differences observed in the hippocampus of adult and aged mice in the presence and absence of the xc- system, a metabolomic analysis was carried out which generated a detailed metabolic profile of the hippocampus of the different groups of mice.

KB: How does the function of the xc – system differ between healthy and diseased brains? Does the function change with age?


A M: Although there is no indication that the function, expression or activity of the xc- system changes with age, the needs of the aging body/brain do. For example, suppression of the xc- system may reduce extracellular glutamate levels in the aged brain, which could be beneficial because glutamate removal may become less efficient with age, leading to toxic accumulation. Additionally, reduced “priming” of the innate immune system as well as metabolic changes in the hippocampus of aged mice with a genetic deletion of xCT, might contribute to the positive effects we observed in aged xCT-/- mice.

KB: The finding that the absence of the xc-system improves brain function and memory in aging mice has been described as “unexpected”. why is this the case?


A M: That their lifespan was increased was the most unexpected finding, as the oxidative change in the plasma cystine/cysteine ​​ratio that was observed in 2005 by H. Sato and colleagues in adult mice lacking antiporter suggested that the aging process of these mice could be accelerated. 8 This hypothesis was based on the observation that in humans, a similar oxidative change occurs with age. 9 The preservation of memory in aged mice lacking the xc-system was, however, the most exciting finding.

KB: Do you think the xc – system could provide a drug target in the future?

A M: We believe the xc-system is a drugged target. However, at the time of writing, there are no specific inhibitors without xc-system off-target effects that can be used live.

KB: What are your next steps to take this research forward?

A M: We are currently exploring several pathways that are altered by the aging process and that could be affected by a deficiency in the xc system. This will help us understand the mechanism(s) underlying our observations and which molecular pathways might be crucial to maintaining our cognitive functions as we age.

Professor Ann Massie was talking to Katie Brighton, science writer at Technology Networks.

References:

1. De Bundel D, Schallier A, Loyens E, et al. Loss of the xc− system does not induce oxidative stress but decreases extracellular glutamate in the hippocampus and influences spatial working memory and susceptibility to limbic seizures. J Neurosci. 2011;31(15):5792-5803. doi: 10.1523/JNEUROSCI.5465-10.2011

2. Massie A, Schallier A, Kim SW, et al. Dopaminergic neurons of xc-deficient mice are highly protected against 6-hydroxydopamine-induced toxicity. FASB J. 2011;25(4):1359-1369. doi: 10.1096/fj.10-177212

3. Albertini G, Deneyer L, Ottestad-Hansen S, et al. Genetic deletion of xCT attenuates peripheral and central inflammation and attenuates LPS-induced disease and depression-like behavior in mice. Glia. 2018;66(9):1845-1861. doi:10.1002/glia.23343

4. Sprimont L, Janssen P, De Swert K, et al. Suppression of the cystine-glutamate antiporter accelerates motor recovery and improves histological findings after spinal cord injury in mice. Scientific representative. 2021;11(1):12227. doi: 10.1038/s41598-021-91698-y

5. Mesci P, Zaïdi S, Lobsiger CS, et al. The xC− system is a mediator of microglial function and its deletion slows symptoms in mice with amyotrophic lateral sclerosis. Brain. 2015;138(1):53-68. doi:10.1093/brain/awu312

6. Leclercq K, Liefferinge JV, Albertini G, et al. Anticonvulsant and antiepileptogenic effects of inactivation of the xc− system in models of chronic epilepsy. Epilepsy. 2019;60(7):1412-1423. doi:10.1111/epi.16055

7. Bentea E, De Pauw L, Verbruggen L, et al. Aged xCT-deficient mice are less susceptible to nigrostriatal pathway degeneration induced by lactacystin, but not by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Frontal cell neuroscience. 2021;15:796635. doi: 10.3389/fncel.2021.796635

8. Sato H, Shiiya A, Kimata M, et al. Redox imbalance in cystine/glutamate transporter deficient mice. J Biol Chem. 2005;280(45):37423-37429. doi: 10.1074/jbc.M506439200

9. Jones DP, Mody VC, Carlson JL, Lynn MJ, Sternberg P. Redox analysis of human plasma can separate the pro-oxidant events of aging from the decline of antioxidant defenses. Biol Med Free Radic. 2002;33(9):1290-1300. doi: 10.1016/S0891-5849(02)01040-7