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  • The preferential expression of ALOX B in

    2023-01-16

    The preferential expression of ALOX15B in human macrophages may explain why human genetic studies investigating the association of ALOX15 with cardiovascular disease did not show consistent results. Two rare functional polymorphisms have been characterized in the ALOX15 gene, which leads to increased (c. −292C>T) [34] and reduced (T560M) [10] enzyme activity, respectively. While the activating c. −292C>T polymorphism showed a trend towards an atheroprotective effect in a small case–control study for coronary artery disease, the inactivating T560M polymorphism was associated with a significantly increased risk for coronary artery disease in the ADVANCE study, indicating that ALOX15 may be anti-inflammatory and anti-atherogenic in humans [9], [10]. However, corroboration of such an atheroprotective effect of the ALOX15 gene failed in a larger case–control study on myocardial infarction possibly because of the low frequency of the T560M polymorphism [11]. So far all large Caucasian study samples investigating the association of the inactivating polymorphism (T560M) in ALOX15 showed a similar risk increase which was, however, not significant in two of the studies [10], [11]. In light of our results which emphasize that ALOX15B is the major 12/15-lipoxygenase in human macrophages, further research on the role of the ALOX15B gene in human atherosclerosis would be warranted.
    Acknowledgments This work was supported by the Swiss National Science Foundation.
    Introduction Lipoxygenases (LOs) are not only key Azacyclonol sale in the biosynthesis of a variety of biologically active lipids but also, by directly oxidizing lipid components in cell membranes, generate inducers of structural changes that play a role in the maturation and differentiation of various cell types [1]. While the mouse has seven different lipoxygenase genes, only five have been found in humans. Nomenclature for the different LOs is based on the positional specificity of their substrate oxygenation. For example, the 12LO oxygenates the arachidonate substrate at carbon in position 12, whereas the 5LO modifies carbon 5. When more than one LO is present in the same species, they are named after the prototypical tissue of occurrence. The five human LOs include 5LO, 12LO with platelet-type and leukocyte-type isoforms, and 15LO which is further separated into the reticulocyte- or leukocyte-type, 15LO-1, and the epidermis-type, 15LO-2 2, 3. While some LOs exclusively form one compound from their substrate, others possess dual specificity [4]. For example, leukocyte-type 12LO and reticulocyte-type 15LO-1 catalyze both carbon 12 and carbon 15 oxygenation to form two products: 12- and 15-hydroxyeicosatetraenoic acid (12-HETE and 15-HETE), and for this reason they are also referred to as 12/15LO 5, 6. Among the dual-specificity LOs is arachidonate 12LO, the brain isoform originally isolated from rat brain, which generates both 12-HETE and 15-HETE 7, 8. LOs are widely expressed throughout many tissues and have been implicated in several different diseases including diabetes (both types 1 and 2), atherosclerosis, renal disease, and obesity 9, 10. Recently, LOs have been also implicated in some disorders of the central nervous system (CNS), including AD. In this article we provide an overview of this enzymatic pathway in the context of AD pathogenesis by exploring its contribution to the molecular and behavioral insults seen in the disease. In addition, we present a rationale for why targeting 12/15LO could lead to viable therapeutics relevant not only for AD but also for other diseases of the CNS.
    AD Characterized by profound and irreversible memory impairment and cognitive deficits, AD is the most common neurodegenerative dementia. The disease is a global dilemma, with over 30 million patients worldwide and an economic burden exceeding half a trillion USD. Epidemiological studies suggest that 11% of those aged 65 years and older, and almost one third of those 85 and older, have some form of the disease [11]. Because population demographics predict a worldwide increase in those aged 65 and older in the next 15 years, AD is a serious public health challenge. However, current therapeutic strategies are very limited for AD patients and do not modify disease course 12, 13. Therefore, investigation of new therapeutic targets that address multiple different facets of the AD phenotype and related pathophysiology must be actively sought to help to address this problem.