Oxylipins, aging and Alzheimer's disease

Alzheimer’s disease (AD) accounts for approximately two‑thirds of all dementia cases, and its prevalence is projected to triple by 2050, underscoring the urgent need to identify new biological pathways that influence neurodegeneration. Emerging human studies suggest a causal relationship between dietary omega‑3 and omega‑6 fatty acids and brain aging, yet the molecular mechanisms underlying these effects remain poorly understood. This proposal seeks to clarify how metabolites derived from omega‑3 and omega‑6 polyunsaturated fatty acids (PUFAs) contribute to Alzheimer’s disease and age‑related neurodegeneration.

Omega‑3 and omega‑6 PUFAs are metabolized through the arachidonic acid cascade to produce hundreds of bioactive lipid‑signaling molecules known as oxylipins. These molecules regulate key physiological processes, including inflammation, angiogenesis, blood pressure, and fibrosis, and their levels change significantly during disease progression. Recent evidence suggests that specific oxylipins may play an important role in AD pathology. Because amyloid‑β (Aβ) plaques, tau aggregation, and aging are central features and risk factors of Alzheimer’s disease, this study hypothesizes that these processes alter oxylipin profiles in vivo, thereby influencing neuronal health.

To test this hypothesis, the project employs a multidisciplinary approach combining chemistry, neurobiology, and Alzheimer’s disease research. Using the model organism Caenorhabditis elegans, researchers will first establish relationships between endogenous cytochrome P450‑derived PUFA metabolites and Aβ‑, tau‑, and aging‑induced neurodegeneration. They will then assess how specific oxylipins affect neurodegenerative outcomes. Advanced liquid chromatography–mass spectrometry will be used to quantify oxylipins across the organism’s lifespan and in transgenic strains expressing Aβ and tau. Ultimately, this work aims to identify a novel lipid‑mediated pathway relevant to aging and neurodegeneration and to explain how dietary PUFAs influence brain health.