<b>The Role of Acrolein and Aldehyde Dehydrogenase 2 in EAE Mice</b>

<p dir="ltr">Despite the widespread incidence and debilitating nature of Multiple Sclerosis (MS), an understanding of its pathology and current treatment options remains limited. Previous efforts in our lab have identified acrolein, a toxic reactive aldehyde, as a promoter of oxidative stress and a direct instigator of axonal damage and demyelination, contributing to the primary hallmarks of MS pathology. Recent experiments in an animal model of MS, Experimental Autoimmune Encephalomyelitis (EAE), have demonstrated acrolein scavenging as a viable and promising treatment option for MS. In Chapter 2, we investigate and further establish the clinical relevance of utilizing acrolein scavengers, specifically Hydralazine (HZ), Phenelzine (PZ), and Alda-1, an enhancer of our innate acrolein-scavenging enzyme ALDH2, to mitigate motor deficits and inflammation in EAE mice. Furthermore, we utilize a clinically relevant genotype of ALDH2 deficiency, ALDH2*2, to investigate the pathological consequences of acrolein accumulation in EAE, which is studied in-depth in Chapter 3. Finally, Chapter 4 seeks to address whether a synergistic combination can be achieved between the exogenous and endogenous mechanisms of HZ and Alda-1 treatment, in addition to investigating their efficacy in both the WT and ALDH2*2 genotype. Our findings serve to consolidate the critical role of acrolein in EAE pathology, demonstrating the potent ability of acrolein scavengers to alleviate symptoms, while ALDH2*2 contributes to a significant exacerbation of EAE pathology. Our results highlight a need for future studies and data availability regarding the connection between ALDH2*2 individuals and MS, as this may prove to be a significant factor in tailoring treatments for these individuals. Furthermore, treatment with acrolein scavengers alone appears incapable of fully restoring symptoms in EAE mice, indicating a need for future investigations into additional treatment options to reverse neuronal damage.</p>