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 Aß 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 Aß 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 Aß-, tau-and aging-
induced neurodegeneration and; 2) determine the effect(s) of specific oxylipins on Aß-, tau-and aging induced
neurodegeneration. We will use Caenorhabditis elegans (C. elegans) as a model organism to study the effect of
Aß 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 Aß and tau. We will test the effect of oxylipins that are significantly affected by deposition of Aß and
tau and aging in neurodegenerative assays using transgenic strains that overexpress Aß 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.