Integrated Pathways of COX-2 and mTOR: Roles in Cell Sensing and Alzheimer’s Disease

Abstract

Cyclooxygenases (COX) are enzymes catalyzing arachidonic acid into prostanoids. COX exists in three isoforms: COX-1, 2, and 3. COX-1 and COX-2 have been widely studied in order to explore and understand their involvement in Alzheimer's disease (AD), a progressive neuroinflammatory dementia. COX-2 was traditionally viewed to be expressed only under pathological conditions and to have detrimental effects in AD pathophysiology and neurodegeneration. However, an increasing number of reports point to much more complex roles of COX-2 in AD. Mammalian/mechanistic target of rapamycin (mTOR) has been considered as a hub which integrates multiple signaling cascades, some of which are also involved in AD progression. COX-2 and mTOR are both involved in environmental sensing, growth, and metabolic processes of the cell. They are also known to act in cooperation in many different cancers and thus, their role together in normal cellular functions as well as AD has been explored in this review. Some of the therapeutic approaches targeting COX-2 and mTOR in AD and cancer are also discussed.

Effect of the MAGL/FAAH Dual Inhibitor JZL-195 on Streptozotocin-Induced Alzheimer’s Disease-like Sporadic Dementia in Mice with an Emphasis on Aβ, HSP-70, Neuroinflammation, and Oxidative Stress

“…This result can also be supported by a previously reported study carried out by Nomura and co-workers whereby they demonstrated that the hydrolysis of 2-AG and AEA generated arachidonic acid (AA) in the brain, which is a major precursor for the COX-mediated biosynthesis of prostaglandins that promote neuroinflammation . 2-AG mediated its response by activating CB1 receptors, which inhibit phosphorylation of the ERK1/p38MAPK/NF-κB pathway and therefore reduce the expression of the COX enzyme. , Moreover, an increase in the pro-inflammatory cytokine level in the brain is also linked to the free radical formation and mitochondrial dysfunction in neurodegenerative diseases . Corresponding to these findings of increased oxidative stress due to STZ injection in the brain, we also determined the levels of TBARS, CAT, and SOD.…”

“…61 2-AG mediated its response by activating CB1 receptors, which inhibit phosphorylation of the ERK1/p38MAPK/NF-κB pathway and therefore reduce the expression of the COX enzyme. 62,63 Moreover, an increase in the pro-inflammatory cytokine level in the brain is also linked to the free radical formation and mitochondrial dysfunction in neurodegenerative diseases. 38 Corresponding to these findings of increased oxidative stress due to STZ injection in the brain, we also determined the levels of TBARS, CAT, and SOD.…”

Combined royal jelly 10-hydroxydecanoic acid and aspirin has a synergistic effect against memory deficit and neuroinflammation

“…Many studies have depicted the role of COX-2 in inflammation and AD. 45 In line with a previous study, 46 our results showed that contrary to COX-2 which was elevated upon LPS stimulation, the COX-1 mRNA and protein levels in the BV-2 cells were decreased after the LPS treatment. Conversely, some studies also reported that COX-1 is activated by LPS in PC12 cells.…”

Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases

“…COX-2 is stimulated by inflammatory components such as cytokines, TNF-α, IL-1, and IL-2 and has been documented for its combined expression in some cell masses of the brain [ 47 ]. Studies reported that COX-2 expression is deficient in astrocytes [ 48 ], increases in the early phases of the disease [ 47 , 48 ], and is principally expressed in pyramidal neurons [ 49 ].…”