Abstract
Docosahexaenoic acid (DHA) is enriched in membrane phospholipids of the central nervous system (CNS) and has a role in aging and neuropsychiatric disorders. DHA is metabolized by the enzyme Alox15 to 17S-hydroxy-DHA, which is then converted to 7S-hydroperoxy,17S-hydroxy-DHA by a 5-lipoxygenase, and thence via epoxy intermediates to the anti-inflammatory molecule, resolvin D1 (RvD1 or 7S,8R,17S-trihydroxy-docosa-Z,9E,11E,13Z,15E,19Z-hexaenoic acid). In this study, we investigated the distribution and function of Alox15 in the CNS. RT-PCR of the CNS showed that the prefrontal cortex exhibits the highest Alox15 mRNA expression level, followed by the parietal association cortex and secondary auditory cortex, olfactory bulb, motor and somatosensory cortices, and the hippocampus. Western blot analysis was consistent with RT-PCR data, in that the prefrontal cortex, cerebral cortex, hippocampus, and olfactory bulb had high Alox15 protein expression. Immunohistochemistry showed moderate staining in the olfactory bulb, cerebral cortex, septum, striatum, cerebellar cortex, cochlear nuclei, spinal trigeminal nucleus, and dorsal horn of the spinal cord. Immuno-electron microscopy showed localization of Alox15 in dendrites, in the prefrontal cortex. Liquid chromatography mass spectrometry analysis showed significant decrease in resolvin D1 levels in the prefrontal cortex after inhibition or antisense knockdown of Alox15. Alox15 inhibition or antisense knockdown in the prefrontal cortex also blocked long-term potentiation of the hippocampo-prefrontal cortex pathway and increased errors in alternation, in the T-maze test. They indicate that Alox15 processing of DHA contributes to production of resolvin D1 and LTP at hippocampo-prefrontal cortical synapses and associated spatial working memory performance. Together, results provide evidence for a key role of anti-inflammatory molecules generated by Alox15 and DHA, such as resolvin D1, in memory. They suggest that neuroinflammatory brain disorders and chronic neurodegeneration may ‘drain’ anti-inflammatory molecules that are necessary for normal neuronal signaling, and compromise cognition.
Highlights
Lipoxygenases (EC 1.13.11) are a superfamily of oxidoreductive enzymes that contain a nonheme iron and catalyze the incorporation of two atoms of oxygen into a single donor, polyunsaturated fatty acids (PUFA) containing a cis,cis-1,4pentadiene structure [1, 2]
Real-time retention tine (RT)-PCR results indicate that the prefrontal cortex exhibits the highest mRNA expression level with approximately 25-fold greater expression than the cerebellum, followed by the parietal association cortex and secondary auditory cortex with over 15-fold greater expression than the cerebellum, olfactory bulb with approximately 15fold greater expression than the cerebellum, motor and somatosensory cortices, and the hippocampus
The expression levels of reticulocyte-type Alox15 across the central nervous system (CNS) were studied via real-time RT-PCR and Western blot
Summary
Lipoxygenases (EC 1.13.11) are a superfamily of oxidoreductive enzymes that contain a nonheme iron and catalyze the incorporation of two atoms of oxygen into a single donor, polyunsaturated fatty acids (PUFA) containing a cis,cis-1,4pentadiene structure [1, 2]. There are two isoforms of the 15-lipoxygenase enzyme, the type 1 (Alox15), known in rodents as leukocyte-type and in humans as reticulocyte-type, and type 2 (Alox15B) [5], both of which regulate the production of fatty acid hydroperoxides [6, 7]. Human reticulocyte-type Alox, known as arachidonate 15lipoxygenase (Alox15), is a 75 kDa enzyme made up of a single chain of amino acids. The Alox gene is found on human chromosome 17 It has 10 tandem repeats of a motif rich in pyrimidine in its 3′-untranslated region, which regulate enzyme expression inhibiting Alox translation through association with the regulatory proteins, heterogeneous ribonucleoprotein K, and heterogeneous ribonucleoprotein E1 [8]
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