Oxylipins, aging and Alzheimer’s disease

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Alzheimer’s disease (AD) comprises about two-thirds of the total dementia cases, and the number of AD cases is expected to triple by 2050. Identifying a new pathway that modulates AD will not only improve our understanding of the mechanism behind neurodegeneration, but will also significantly improve the quality of life of the aged population. Recent human studies revealed a causal relationship between the levels of omega-3 and omega-6 dietary lipids and aging of the brain. However, the specific pathway(s) behind such effects remains largely unknown. The overall goal of this proposal is to elucidate the role of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) metabolites in AD. Metabolism of omega-3 and omega-6 PUFAs generates hundreds of lipid-signaling molecules called oxylipins through the arachidonic acid (AA) cascade. These oxylipins play a homeostatic role in inflammation, blood pressure regulation, angiogenesis, and fibrosis, and their in vivo levels are significantly affected by disease progression. Furthermore, recent studies suggested that specific oxylipins may play an important role in AD. The deposition of Aβ and tau are hallmarks of AD, and aging remains one of the key risk factors of AD. Therefore, in this proposal, we hypothesize that deposition of Aβ and tau and aging modulate the in vivo oxylipin levels, which affects the neuronal health of animals. To test our hypothesis, we will develop a multidisciplinary approach by assembling expertise from organic and analytical chemists, neurobiologists, AD researchers and the use of a model organism. We will 1) establish the relationship between endogenous levels of CYP450 PUFA metabolites and the effect of Aβ-, tau-and aging- induced neurodegeneration and; 2) determine the effect(s) of specific oxylipins on Aβ-, tau-and aging induced neurodegeneration. We will use Caenorhabditis elegans (C. elegans) as a model organism to study the effect of Aβ and tau, and aging on PUFA metabolism because of the ease of generating large age-synchronized populations, and the number of established genetic tools available to carry out this research. Furthermore, many aging and neurodegenerative pathways and oxylipin pathways are conserved between C. elegans and humans. We will use state-of-the-art ultra-performance liquid chromatography coupled with tandem mass spectrometry to determine oxylipins levels in C. elegans over the lifespan of the organism and in transgenic strains that overexpress Aβ and tau. We will test the effect of oxylipins that are significantly affected by deposition of Aβ and tau and aging in neurodegenerative assays using transgenic strains that overexpress Aβ and tau. Upon success of this project, we could identify a new pathway important for aging and neurodegeneration research. Our results could also explain the effect(s) of omega-3 and omega-6 PUFAs on aging.