sarparast, Morteza et al. (2021) International Worm Meeting "Soluble Epoxide Hydrolase Inhibitor, AUDA, Recuses Neurodegeneration Induced by Amyloid beta and Tau"

Sarparast, Morteza, Zhang, Fan, Ramirez, Leslie, Stephen Lee, Kin Sing, K. Alan, Jamie, Kessler, Benjamin

[International Worm Meeting, 2021]

According to a United Nations report, the percentage of the population over the age of 65 is expected to increase from approximately 9% (2019), to roughly 20% by 2050. With this demographic change, we can expect a coinciding increased incidence of age-related neurodegenerative diseases (ND), including Alzheimer's Disease (AD), for which there is no cure. The two hallmark pathologies of AD are the deposition of the amyloid beta (Abeta) and the neurofibrillary tangles of the microtubule-binding protein tau. Recent evidence suggests that increasing the epoxy-metabolites of polyunsaturated fatty acids (PUFAs) through pharmacological inhibition or genetic knock-out of soluble epoxide hydrolase (sEH), which metabolizes epoxy-PUFAs, could be an effective strategy in limiting AD neurodegeneration. Considering this, we seek to investigate the effect(s) of epoxy-PUFAs on tau- and Abeta-induced neurodegeneration using Caenorhabditis elegans (C. elegans). The transgenic Tau (CK1441) and Abeta (CL2355) mutants show neurodegenerative behavior such as slow thrashing and decreased locomotion speed, respectively, and both strains show hypersensitivity to serotonin. Interestingly, supplementation of HE inhibitor, 12-[[(tricyclo[3.3.1.13.7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid (AUDA), rescues neurodegeneration in both transgenic strains. Our results suggested that specific epoxy-PUFAs significantly affect neurodegeneration, in particular those mediated by deposition of Abeta and/or tau, and the mechanistic studies on how EH inhibition alleviates neurodegeneration induced by Abeta and/ or tau are underway.

Kessler, Benjamin et al. (2021) International Worm Meeting "Disrupting Polyunsaturated Fatty Acid Biosynthesis Modulates Lifespan and Healthspan"

Sarparast, Morteza, Lee, Kin Sing Stephen, Dattmore, Devon, Alan, Jamie K., Kessler, Benjamin, Zhang, Fan

[International Worm Meeting, 2021]

Specific omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have protective effects against aging-related conditions such as cardiovascular disease, inflammation, and neurodegenerative diseases. However, it is unclear which PUFAs are required in the diet and how they affect human health and disease. This study will investigate the physiological roles of individual PUFAs in order to pharmacologically and dietarily promote healthy aging. We will use fatty acid desaturase enzyme knockout transgenic C. elegans strains to assess the in vivo effects of PUFAs on the aging process. This investigation will create a dataset that includes lifespan and healthspan data (as determined by thrashing and/or egg laying) for every available fatty acid desaturase enzyme genetic knockout in the worm. Additionally, lipidomic or metabolic analysis will be used to assess the lipidome of key strains. We hypothesize that specific PUFAs modulate physiological processes through their corresponding downstream metabolites' role in lipid signaling. Our data showed that mutants with genetically disrupted PUFA biosynthesis displayed a decreased median lifespan, poor physical fitness, and altered egg laying patterns. Interestingly, our results from several mutants are different from published data involving the use of FuDR, a chemical that prevents progeny. It is expected that lipidomic analysis of the knockout worms will reveal that our in vivo observations are associated with an altered lipid panel, especially downstream metabolites. Our data suggest that genetically altering endogenous levels of PUFAs modulates lifespan and healthspan. However, specifically limiting omega-3 PUFA biosynthesis has a rescuing effect on healthspan. Investigating these metabolic pathways may elucidate novel drug targets that could revolutionize chronic disease treatment and prevention.

Lee, Kin Sing Stephen et al. (2021) International Worm Meeting "The Effect of Cytochrome P450 Metabolites of Dietary Polyunsaturated Fatty Acids on Age-Associated Neurodegeneration."

Kessler, Benjamin, Pourmand, Elham, Lee, Kin Sing Stephen, Sarparast, Morteza, Alan, Jamie, Ramirez, Leslie, Zhang, Fan

[International Worm Meeting, 2021]

By 2035, the population older than 65 is projected to be 21.3% (78 million) increasing from 15.2% in 2016. Most elderly patients eventually develop some degree of cognitive dysfunction, and Alzheimer's disease alone affects almost 33% to 50% of the population over 85. As such, there is an unmet medical need to identify pathways that could curb neurodegeneration. Such a discovery significantly improves the quality of life for elderly patients. Recent research demonstrated that inhibition of cytochrome P450 (CYP) metabolism of dietary polyunsaturated fatty acids (PUFAs) is beneficial for several neurodegenerative diseases, including Parkinson's and Alzheimer's diseases. However, the detailed mechanism by which specific PUFA CYP metabolites responsible for such beneficial effects remains largely unknown. To tackle this problem, we apply a multidisciplinary approach to investigate the underlying mechanism and identify the signaling molecules responsible for the effects of PUFA CYP metabolites on neurodegeneration. We will use C. elegans as an animal model because it has been used to investigate neurodegeneration mechanism for more than a decade. Specifically, in this presentation, we will present our efforts in developing and applying different chemical tools to study the mechanism of how PUFA CYP metabolites affect neurodegeneration in different transgenic C. elegans strains. We found that inhibition of epoxide hydrolase in C. elegans rescues the neurodegenerative phenotypes in the strains expressing either amyloid-beta or tau, which are similar to what has been found in the murine Alzheimer's disease amyloidosis or tauopathy models. We also demonstrated that a specific omega-6 PUFA CYP metabolite actually induces neurodegeneration. This result is interesting as most studies suggested that in general, PUFA CYP metabolites are beneficial for neurodegenerative disease. Our studies open new directions for neurodegeneration and C. elegans research, and further mechanistic studies are currently being undertaken in our laboratory.