Distinct Lipid Mediator Pathways Contribute to Neuroinflammation in the Temporal and Occipital Cortex of Alzheimer’s Disease Subjects

Davide Vacondio,Loet Coenen，Helga E. de Vries,Nienke M. de Wit

crossref（2024）

Biomedical Primate Research Centre | Center for Proteomics and Metabolomics

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Abstract

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.

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【要点】：本研究揭示了阿尔茨海默病（AD）患者枕叶和颞叶皮质中不同生物活性脂质介质（LMs）代谢途径的差异性激活，为AD的病理机制提供了新见解，并指出了潜在的治疗靶点。

【方法】：采用靶向液相色谱-串联质谱技术分析人类AD和非神经系统疾病对照大脑组织中的LMs。

【实验】：通过实验，研究者在AD患者的枕叶皮质中检测到环氧合酶（COX）-1/2途径的激活，并在颞叶皮质中发现脂氧合酶（LOX）途径，尤其是5-LOX的激活。相关性分析显示5-LOX来源的LMs与微胶质细胞活化呈正相关。研究还发现，AD患者大脑中与淀粉样斑块相关的微胶质细胞中5-LOX及其激活蛋白（FLAP）的表达增加。数据集名称未在文中提及。