Distinct lipid mediator pathways contribute to neuroinflammation in the temporal and occipital cortex of Alzheimer’s disease subjects

Bioactive lipid mediators (LMs) have been implicated in Alzheimer’s disease (AD), but their involvement in disease pathogenesis is poorly understood. Using targeted liquid chromatography-tandem mass spectrometry on human AD and non-neurological control brain tissue, we identified a differential activation of arachidonic acid (AA) metabolism in the occipital and temporal cortex of AD subjects. The cyclooxygenase (COX)-1/2 pathway was activated in the occipital cortex and associated with increased expression of neuronal COX-2. Contrarily, in the temporal cortex the lipoxygenases (LOX) pathways, mainly 5-LOX, were activated. Association analysis revealed a positive correlation between 5-LOX-derived LMs and microglia activation. In line, the expression of 5-LOX and its activating protein (FLAP) was increased in disease-associated microglia near amyloid plaques in AD brains. We propose that the latter process is partially mediated by transforming growth factor-β1 and can be abrogated by FLAP inhibition. Our results indicate a differential response in AD brains associated with an AA-derived LM profile, driven by distinct LM biosynthetic pathways. These findings advance our understanding of the role of LMs in the pathophysiology of AD and provide new therapeutic targets to combat disease progression.