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AA147 Alleviates Symptoms in a Mouse Model of Multiple Sclerosis by Reducing Oligodendrocyte Loss
Metin Aksu1, Kevin Kaschke1, Joseph R Podojil2
1Department of Biology, Loyola University Chicago, Chicago, Illinois, USA.
Abstract:
Inflammation-induced oligodendrocyte death and CNS demyelination are key features of multiple sclerosis (MS). Inflammation-triggered endoplasmic reticulum (ER) stress and oxidative stress promote tissue damage in MS and in its preclinical animal model, experimental autoimmune encephalitis (EAE). Compound AA147 is a potent activator of the ATF6 signaling arm of the unfolded protein response (UPR) that can also induce antioxidant signaling through activation of the NRF2 pathway in neuronal cells. Previous work showed that AA147 protects multiple tissues against ischemia/reperfusion damage through ATF6 and/or NRF2 activation; however, its therapeutic potential in neuroinflammatory disorders remains unexplored. Here, we demonstrate that AA147 ameliorated the clinical symptoms of EAE and reduced ER stress, oligodendrocyte loss, and demyelination. Additionally, AA147 suppressed T cells in the CNS without altering the peripheral immune response. Importantly, AA147 significantly increased the expressions of Grp78, an ATF6 target gene, in oligodendrocytes, while enhancing levels of Grp78 as well as Ho-1, an NRF2 target gene, in microglia. In cultured oligodendrocytes, AA147 promoted nuclear translocation of ATF6, but not NRF2. Intriguingly, AA147 altered the microglia activation profile, possibly by triggering the NRF2 pathway. AA147 was not therapeutically beneficial during the acute EAE stage in mice lacking ATF6 in oligodendrocytes, indicating that protection primarily involves ATF6 activation in these cells. Overall, our results suggest AA147 as a potential therapeutic opportunity for MS by promoting oligodendrocyte survival and regulating microglia status through distinct mechanisms.
Insights
Compound AA147 reduces multiple sclerosis (MS) symptoms by protecting oligodendrocytes from ER stress and demyelination. It targets central nervous system inflammation, suggesting potential as an MS therapy.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Cellular Stress Response
Background:
- Multiple sclerosis (MS) involves oligodendrocyte death and central nervous system (CNS) demyelination.
- Endoplasmic reticulum (ER) stress and oxidative stress exacerbate MS pathology.
- Compound AA147 activates unfolded protein response (UPR) and antioxidant pathways.
Purpose of the Study:
- To explore the therapeutic potential of AA147 in neuroinflammatory disorders, specifically MS.
- To investigate AA147's effects on ER stress, oligodendrocyte survival, and demyelination in experimental autoimmune encephalitis (EAE).
Main Methods:
- Administration of AA147 in a preclinical mouse model of MS (EAE).
- Assessment of clinical symptoms, ER stress markers (Grp78), oxidative stress markers (Ho-1), oligodendrocyte survival, and demyelination.
- Analysis of T cell responses in the CNS and periphery.
- Investigation of AA147's mechanism of action via ATF6 and NRF2 pathways in oligodendrocytes and microglia.
- Studies in EAE mice lacking ATF6 in oligodendrocytes.
Main Results:
- AA147 ameliorated EAE clinical symptoms, reduced ER stress, oligodendrocyte loss, and demyelination.
- AA147 suppressed CNS T cells without affecting peripheral immunity.
- AA147 upregulated ATF6 target Grp78 in oligodendrocytes and NRF2 target Ho-1 in microglia.
- AA147 promoted ATF6 nuclear translocation in oligodendrocytes and modulated microglia activation.
- AA147's therapeutic benefit in EAE was dependent on ATF6 in oligodendrocytes.
Conclusions:
- AA147 demonstrates therapeutic potential for MS by protecting oligodendrocytes via ATF6 activation.
- AA147 may also regulate microglia function through the NRF2 pathway.
- AA147 offers a promising therapeutic strategy for MS by preserving oligodendrocyte survival and modulating neuroinflammation.
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