The cystine/glutamate antiporter system xc‾ as modulator of systemic inflammation-induced neurological dysfunction in healthy and pathological aging

Research output: ThesisPhD Thesis

Abstract

For the first time in history, the number of people aged 65 years or older outnumber children younger than 5 years. The added years to the overall life expectancy coincide with an increase in age-related diseases, e.g. neurodegenerative diseases, cancer and diabetes. It is thus of utmost importance to find a way to spend these additional years in good health. Gathering more insight in healthy physiological aging, will also increase our knowledge on the pathological aging process.

The cystine/glutamate antiporter system xc-, was shown to be an important modulator of brain extracellular glutamate levels -and thus of glutamatergic neurotransmission, glutamate-sensitive behavior and excitotoxicity- as well as (neuro)inflammation. Deletion of the specific subunit xCT (xCT-/-mice), results in attenuated (neuro)inflammatory responses to a peripheral lipopolysaccharide (LPS) injection, as well as protection against toxin-induced neurodegeneration in mouse models for Parkinson’s disease (PD). Moreover, the deletion of xCT leads to lifespan extension, with protection against age-related hippocampus-dependent memory loss and exacerbated inflammatory responses(i.e. inflammaging). Therefore, system xc- might be an interesting target to prevent neurodegeneration and cognitive decline in healthy and pathological aging.

This thesis investigates whether the aforementioned beneficial effects of xCT deletion in PD models can be replicated in a more clinically relevant progressive and chronic model, i.e. the aged MPTP mouse model, and whether the protective effects at the level of the aging hippocampus can be generalized to the most common neurodegenerative disorder, i.e. Alzheimer’s disease (AD). Furthermore, we studied whether the origin of these beneficial effects can be found in the peripheral immune system or in the central nervous system (CNS). The lack of specific inhibitors for system xc- puts a break on clinical translation. If selectively targeting system xc- in the periphery might be sufficient, this would facilitate the search for novel strategies to counter pathological aging.

The first part of this thesis focussed on the effect of xCT deletion in the MPTP (1-methyl-4-phenyl1,2,3,6-tetrahydropyridine) mouse model for PD. Previous findings showed that, contrary to observations in other acute PD mouse models, adult xCT-/- mice were not protected against MPTPinduced neurodegeneration. However, considering PD has a disease onset at an advanced age and agedependent protection was found in other models, we evaluated the effect of xCT deletion on MPTPinduced toxicity in aged mice. Our findings indicate, however, that the deletion of xCT does not protect aged mice against MPTP-induced nigrostriatal degeneration.

Given the protection against age-related hippocampal impairment in the absence of xCT, we evaluated whether this would also apply to the corticostriatal pathway of aged xCT-/- mice. Although adult xCT-/-mice had impaired corticostriatal neurotransmission, combined with abnormal repetitive and social behavior, this was not detected in aged xCT-/- mice compared to age-matched wild type (WT) littermates. The decreased glutamate levels observed in the corticostriatal synapse of adult xCT-/-mice, did not persist in aged xCT-/- mice. While being speculative, we hypothesize that this might be the reason why corticostriatal neurotransmission and social behavior are no longer impaired by the absence of xCT in aged mice.

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Next, we used the 5XFAD mouse model to investigate whether the beneficial effect on hippocampal function in aged mice can be generalized to a model for AD. By cross-breeding the 5XFAD mice with xCT-/- mice, we generated the 5XFAD-xCT mouse model that allowed us to evaluate the effect of xCT deletion on AD progression. Besides the 5XFAD+/0 (heterozygous) mice, our research also included the 5XFAD+/+ (homozygous) mice. The presence of the 5XFAD mutations induced behavioral impairment in both male and female mice, which became mainly evident at the age of 6 months and was more pronounced in female mice. However, overall only moderate effects of the deletion of xCT were detected. Strikingly, the microglial activation and amyloid plaque load in the hippocampus of 5XFAD+/+ xCT-/- mice were more severe compared to 5XFAD+/+ xCT+/+ mice.

So far, all our research has been performed on congenital xCT-/-mice. To investigate the role of immune cell xCT in age-related hippocampal dysfunction, chimeric mice were generated using bone marrow transplantations (BMT). Our BMT procedure that was optimized to obtain the highest degree of BM replacement while still maintaining a high percentage of viability of the mice, required the head to be included in the irradiation field (total body irradiation; TBI). We therefore investigated the short- and long-term adverse effects on the brain, such as hippocampus-dependent memory impairment, increased blood-brain barrier (BBB) permeability, cortical microglial activation and impaired neurogenesis. Next, chimeric mice were generated -using our optimized BMT procedure- that express
or lack xCT exclusively on the cells of their peripheral immune system. Yet, besides a slight shift towards less reactive microglia in the dentate gyrus of the hippocampus, we did not observe any major effect of manipulating xCT expression on the immune cells on hippocampal function in middle-aged or aged mice. We therefore concluded that the deletion of xCT specifically on cells of the peripheral immune system is not sufficient to obtain the same protective effects on hippocampal function as seen in aged
congenital xCT-/- mice, neither is the presence of xCT exclusively on immune cells sufficient to induce age-related hippocampal impairment.

Although most of our hypotheses had to be refuted, this PhD work provides important novel insight in
the function of system xc- in healthy and pathological brain function.
Original languageEnglish
Awarding Institution
  • Vrije Universiteit Brussel
Supervisors/Advisors
  • Massie, Ann, Supervisor
  • RIS, Laurence, Co-Supervisor, External person
Award date11 Sep 2024
Publication statusPublished - 2024

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