Non-steroidal Anti-inflammatory Drugs Stimulate Secretion of Non-amyloidogenic Precursor Protein

Abstract

Chronic inflammatory processes are associated with the pathophysiology of Alzheimer's disease (AD), and it has been proposed that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk for AD. Here we report that various NSAIDs, such as the cyclooxygenase inhibitors, nimesulide, ibuprofen and indomethacin, as well as thalidomide (Thal) and its nonteratogenic analogue, supidimide, significantly stimulated the secretion of the non-amyloidogenic ␣-secretase form of the soluble amyloid precursor protein (sAPP␣) into the conditioned media of SH-SY5Y neuroblastoma and PC12 cells. These NSAIDs markedly reduced the levels of the cellular APP holoprotein, further accelerating non-amyloidogenic processes. sAPP␣ release, induced by nimesulide and Thal, was modulated by inhibitors of protein kinase C and Erk mitogen-activated protein (MAP) kinase. Furthermore, in results complementary to the inhibitor studies, we show for the first time that NSAIDs can activate the Erk MAP kinase signaling cascade, thus identifying a novel pharmacology mechanism of NSAIDs. Our findings suggest that NSAIDs and Thal might prove useful to favor non-amyloidogenic APP processing by enhancing ␣-secretase activity, thereby reducing the formation of amyloidogenic derivatives, and therefore are of potential therapeutic value in AD.Alzheimer's disease (AD) 1 pathology is characterized by senile plaques containing ␤-amyloid peptide (A␤), a protein with neurotoxic and glial immune-activating potential (for review, see Refs 1-3). A␤, a 39 -43 amino acid peptide, is derived from a larger transmembrane glycoprotein, the amyloid precursor protein (APP) (4, 5). APP can be processed proteolytically via alternative pathways; cleavages at the N and C termini of A␤ domain by ␤-and ␥-secretases, respectively, lead to the formation of the A␤ peptide. In addition, in the ␣-secretase pathway, the cleavage occurs within the sequence of A␤ peptide and generates a large, secreted form of soluble APP (sAPP), thus precluding the formation of the amyloidogenic A␤ (for recent reviews of APP processing, see Refs. 6 and 7). Because the proportion of APP processed by ␤-secretase versus ␣-secretase may affect the amount of A␤ produced, the regulation of these two pathways may be critically important to the pathogenesis of AD. Previous studies have demonstrated that sAPP secretion could be enhanced by activation of various cell surface receptors, coupled to increased activation of second messenger cascades, including phosphatidylinositol hydrolysis, tyrosine phosphorylation, protein kinase C (PKC), protein kinase A, mitogen-activated protein kinase (MAPK), protein phosphatase 1 and 2B, and calcium (8).In the search for the pathogenic mechanism of AD, much interest has been focused recently on the involvement of inflammatory reactions in AD. A chronic inflammatory response has been described in the brain of AD patients (9), characterized by the presence of activated astrocytes surrounding the senile plaque and activated microglia surrounding and extendin...

Modulation of Amyloid Precursor Protein Cleavage by Cellular Sphingolipids

“…In contrast, we did not observe any alteration in the amount of PKC that translocated to the plasma membrane in the sphingolipid-deficient cells. Although ERK is located in the downstream of the PKC signaling cascade (4,43,46,47), these results suggest that sphingolipid deficiency activates ERK in a pathway different from the PKC pathway. The mechanism by which sphingolipid deficiency causes ERK activation is not yet known; however, it is important to note that many raft-associated proteins mediate signal transduction (20,45,48) and that cholesterol depletion also stimulates ERK activity in neurons (49) and non-neuronal cells (50,51).…”

Nonsteroidal Anti-Inflammatory Drugs Potentiate 1-Methyl-4-phenylpyridinium (MPP+)-Induced Cell Death by Promoting the Intracellular Accumulation of MPP+in PC12 Cells

“…For example, aspirin and salicylate inhibit nuclear factor-B (Kopp and Ghosh, 1994) and the activity of inhibitory B kinase-␤ (Yin et al, 1998). Avramovich et al (2002) demonstrated that NSAIDs can activate extracellular signal-regulated kinase mitogen-activated protein kinase in SH-SY5Y neuroblastoma cells and PC12 cells. Lehmann et al (1997) indicated that several NSAIDs bind and activate peroxisome proliferator-activated receptor ␥ (PPAR␥), a ligand-activated transcription factor.…”

The Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s Disease

“…Although the catabolism of AßPP is constitutive, activation of signal transduction pathways such as the ERK pathway can alter the relative amounts of secreted AßPP and the level of Aß produced. Activation of the ERK pathway, in response to a number of stimuli including nonsteroidal anti-inflammatory drugs, testosterone and estrogen that are of benefit for AD, leads to an increased secreted form of AßPP production [127][128][129][130], which in turn further activates ERK [96], forming a positive feedback loop. Mechanistically, ERK may act to phosphorylate one or more targets that modify AßPP metabolism in a way in favor of the production of sAßPP [126].…”