title: Differential effect of amyloid β on the cytochrome P450 epoxygenase activity in rat brain.
abstract: One of the prominent features of Alzheimer's disease is the excessive accumulation of the protein amyloid beta (Aβ) in certain areas of the brain leading to neurodegeneration. Aβ is cytotoxic and disrupts several cytoprotective pathways. Recent literature has demonstrated that certain cytochrome P450 (CYP) products are neuroprotective, including epoxide metabolites of arachidonic acid (AA), epoxyeicosatrienoic acids (EETs). The action of Aβ with respect to regionally produced EETs in the brain has yet to be defined. Epoxygenases metabolize AA into four regioisomers of EETs (14,15-, 11,12-, 8,9- and 5,6-EET). EETs are rapidly degraded into dihydroxyeicosatrienoic acids (DiHETEs) by soluble epoxide hydrolase (sEH). To determine the effect of Aβ on the epoxygenase activity in different regions of the brain, microsomes were prepared from the cerebrum and cerebellum of adult Sprague-Dawley rats and incubated with 1 and 10 μM Aβ for 30 min after which epoxygenase activity assay was performed. Mass spectrometry indicated that incubation with Aβ reduced 14,15-EET production by 30% as compared to vehicle in the cerebrum, but not in the cerebellum. When we separated the cerebrum into cortex and hippocampus, significant decrease in the production of total EETs and DiHETEs were seen in presence of Aβ (81% and 74%) in the cortex. Moreover, 11,12-EET production was decreased to ∼70% of vehicle in both cortex and hippocampus. Epoxygenase activity in the cultured astrocytes and neurons also showed reduction in total EET and DiHETE production (to 80% and ∼70% of vehicle respectively) in presence of Aβ. Altogether, our data suggest that Aβ reduces epoxygenase activity differentially in a region-specific and cell-specific manner. The reduction of cytoprotective EETs by Aβ in the cerebrum may make it more prone to degeneration than the cerebellum. Further understanding of these interactions will improve our ability to protect against the pathology of Alzheimer's disease.
authors.affiliation: Department of Physiology and Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sarkar
authors.forename: J
authors.initials: J
authors.lastname: Narayanan
authors.forename: D R
authors.initials: DR
authors.lastname: Harder
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D065607:Cytochrome P-450 Enzyme Inhibitors; D018696:Neuroprotective Agents; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid