The Lipoxygenases: Their Regulation and Implication in Alzheimer’s Disease

Abstract

Inflammatory processes and alterations of lipid metabolism play a crucial role in Alzheimer’s disease (AD) and other neurodegenerative disorders. Polyunsaturated fatty acids (PUFA) metabolism impaired by cyclooxygenases (COX-1, COX-2), which are responsible for formation of several eicosanoids, and by lipoxygenases (LOXs) that catalyze the addition of oxygen to linolenic, arachidonic (AA), and docosahexaenoic acids (DHA) and other PUFA leading to formation of bioactive lipids, significantly affects the course of neurodegenerative diseases. Among several isoforms, 5-LOX and 12/15-LOX are especially important in neuroinflammation/neurodegeneration. These two LOXs are regulated by substrate concentration and availability, and by phosphorylation/dephosphorylation through protein kinases PKA, PKC and MAP-kinases, including ERK1/ERK2 and p38. The protein/protein interaction also is involved in the mechanism of 5-LOX regulation through FLAP protein and coactosin-like protein. Moreover, non-heme iron and calcium ions are potent regulators of LOXs. The enzyme activity significantly depends on the cell redox state and is differently regulated by various signaling pathways. 5-LOX and 12/15-LOX convert linolenic acid, AA, and DHA into several bioactive compounds e.g. hydroperoxyeicosatetraenoic acids (5-HPETE, 12S-HPETE, 15S-HPETE), which are reduced to corresponding HETE compounds. These enzymes synthesize several bioactive lipids, e.g. leucotrienes, lipoxins, hepoxilins and docosahexaenoids. 15-LOX is responsible for DHA metabolism into neuroprotectin D1 (NPD1) with significant antiapoptotic properties which is down-regulated in AD. In this review, the regulation and impact of 5-LOX and 12/15-LOX in the pathomechanism of AD is discussed. Moreover, we describe the role of several products of LOXs, which may have significant pro- or anti-inflammatory activity in AD, and the cytoprotective effects of LOX inhibitors.

Impact of Interactions between Ferulic and Chlorogenic Acids on Enzymatic and Non-Enzymatic Lipids Oxidation: An Example of Bread Enriched with Green Coffee Flour

“…Lipoxygenases are enzymes containing non-heme iron and requiring catalytic activation. This activation process involves transformation of non-active iron in ferrous state to iron in ferric state, and this is accomplished by lipid hydroperoxide oxidation [4]. Several independent studies now support the correlation between 5-LOX expression and cancer cell viability, proliferation, cell migration, invasion through extracellular matrix destruction, metastasis, and activation of anti-apoptotic signaling cascades [26].…”

“…Oxygenation of polyunsaturated fatty acids containing a (cis, cis)-1,4-pentadiene system is catalyzed by lipoxygenases (LOXs). The main substrates for LOXs are arachidonic and docosahexaenoic acids released from membrane phospholipids by phospholipases A2 (PLA2) [3,4]. Evidence is accumulating in support of the direct involvement of 5-LOX in the progression of different types of cancer, including prostate, lung, colon, and colorectal cancers [5], (i) a given activity of phenolic compounds studied in vitro (after their isolation from the food) does not have to be in accordance with the same activity demonstrated in the human organism [13].…”

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

“…Arachidonic acid metabolism is catalyzed by cyclooxygenase (COX) and lipoxygenase (LOX). As a result of oxidation of arachidonic acid by COX, a group of prostanoids is formed, while in LOX-catalyzed reactions, leukotrienes, as well as hydroxyeicosatetraenoic acid (HETE), are generated Figure 5 [85]. The resulting compounds, especially those belonging to the eicosanoids: prostaglandins, leukotrienes, thromboxanes, and HETE derivatives show multidirectional effects, mainly associated with the regulation of immune cell function and the modulation of inflammation.…”

Fair‐Weather Friends: Evidence of Lipoxin Dysregulation in Neurodegeneration

“…Post‐mortem analysis of AD patients revealed upregulation of 12/15 LOX and increased levels of the LX precursors 12‐HETE and 15‐HETE in the frontal and temporal lobes . These findings are corroborated by another study which showed increase of the same precursors in cerebrospinal fluid of AD patients, as well as at‐risk patients with mild cognitive impairment, suggesting 12/15 LOX may be involved in the initiation of AD . However, another study has also demonstrated strongly reduced expression and activity of 15‐LOX in the hippocampus of AD patients compared to the hippocampus of matched postmortem controls…”