Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-β aggregation

Thomas, Tom; Nadackal, T.; Thomas, Kavita Elisheba

doi:10.1097/00001756-200110290-00024

Cited by 127 publications

(89 citation statements)

References 26 publications

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“…3B) by decreasing tyrosyl radicals in COX-2. Alternatively, this inhibitory effect of NSAIDs may be a consequence of the direct interactions of NSAIDs with A␤ peptide that have been described (49,50). The concentrations of indomethacin and ibuprofen used in this study are similar to those in the report by Weggen et al (50), who demonstrated that some NSAIDs decrease the production of human A␤1-42.…”

Section: Cox-2 Cross-links A␤supporting

confidence: 81%

Peroxidase Activity of Cyclooxygenase-2 (COX-2) Cross-links β-Amyloid (Aβ) and Generates Aβ-COX-2 Hetero-oligomers That Are Increased in Alzheimer's Disease

Nagano

Huang

Moir

et al. 2004

Journal of Biological Chemistry

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Oxidative stress is associated with the neuropathology of Alzheimer's disease. We have previously shown that human A␤ has the ability to reduce Fe(III) and Cu(II) and produce hydrogen peroxide coupled with these metals, which is correlated with toxicity against primary neuronal cells. Cyclooxygenase (COX)-2 expression is linked to the progression and severity of pathology in AD. COX is a heme-containing enzyme that produces prostaglandins, and the enzyme also possesses peroxidase activity. Here we investigated the possibility of direct interaction between human A␤ and COX-2 being mediated by the peroxidase activity. Human A␤ formed dimers when it was reacted with COX-2 and hydrogen peroxide. Moreover, the peptide formed a cross-linked complex directly with COX-2. Such crosslinking was not observed with rat A␤, and the sole tyrosine residue specific for human A␤ might therefore be the site of cross-linking. Similar complexes of A␤ and COX-2 were detected in post-mortem brain samples in greater amounts in AD tissue than in age-matched controls. COX-2-mediated cross-linking may inhibit A␤ catabolism and possibly generate toxic intracellular forms of oligomeric A␤.

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Section: Cox-2 Cross-links A␤supporting

confidence: 81%

Peroxidase Activity of Cyclooxygenase-2 (COX-2) Cross-links β-Amyloid (Aβ) and Generates Aβ-COX-2 Hetero-oligomers That Are Increased in Alzheimer's Disease

Nagano

Huang

Moir

et al. 2004

Journal of Biological Chemistry

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“…Moreover, these NSAIDs dose-dependently destabilized preformed fAßs. Thomas et al (2001) suggested that the anti-aggregation effect of NSAIDs may be due to their interaction with epitope 3-6 and/or 25-35 in Aß, which are considered crucial to Aß aggregation and neurotoxicity. As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, except the preliminary study where Thomas et al (2001) used the non-physiological short peptide , the effects of NSAIDs on the formation and destabilization of Alzheimer's ß-amyloid fibrils (fAß) in vitro have not been studied in detail.…”

mentioning

confidence: 99%

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

et al. 2005

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The pathogenesis of Alzheimer's disease (AD) is characterized by cerebral deposits of amyloid ß-peptides (Aß) and neurofibrillary tangles which are surrounded by inflammatory cells. Long-term uses of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of developing AD and delay the onset of the disease. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of NSAIDs such as ibuprofen, aspirin, meclofenamic acid sodium salt, diclofenac sodium salt, ketoprofen, flurbiprofen, naproxen, sulindac sulfide and indomethacin on the formation, extension, and destabilization of ß-amyloid fibrils (fAß) at pH 7.5 at 37˚C in vitro. All examined NSAIDs dose-dependently inhibited formation of fAß from fresh Aß(1-40) and Aß(1-42), as well as their extension. Moreover, these NSAIDs dose-dependently destabilized preformed fAßs. The overall activity of the molecules examined was in the following order: ibuprofen ≈ sulindac sulfide ≥ meclofenamic acid sodium salt > aspirin ≈ ketoprofen ≥ flurbiprofen ≈ diclofenac sodium salt > naproxen ≈ indomethacin. Although the mechanisms by which these NSAIDs inhibit fAß formation from Aß, and destabilize preformed fAß in vitro are still unclear, NSAIDs may be promising for the prevention and treatment of AD.

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“…Thus, reducing the level of Ab in the brain and inhibiting the aggregation of Ab are promising strategies for AD therapy [2]. Various compounds such as peptides [3,4], antioxidants [5,6], anti-inflammatory drugs [7], and antibodies [8,9] have been reported to have inhibitory effects on the aggregation of Ab. Furthermore, antibodies against Ab reduce the level of the protein in the brain of APP transgenic mice and inhibit neurotoxicity [10].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the formation of amyloid β‐protein fibrils using biocompatible nanogels as artificial chaperones

et al. 2006

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The formation of fibrils by amyloid b-protein (Ab) is considered as a key step in the pathology of Alzheimer's disease (AD). Inhibiting the aggregation of Ab is a promising approach for AD therapy. In this study, we used biocompatible nanogels composed of a polysaccharide pullulan backbone with hydrophobic cholesterol moieties (cholesterol-bearing pullulan, CHP) as artificial chaperones to inhibit the formation of Ab-(1-42) fibrils with marked amyloidgenic activity and cytotoxicity. The CHPnanogels incorporated up to 6-8 Ab-(1-42) molecules per particle and induced a change in the conformation of Ab from a random coil to a-helix-or b-sheet-rich structure. This structure was stable even after a 24-h incubation at 37°C and the aggregation of Ab-(1-42) was suppressed. Furthermore, the dissociation of the nanogels caused by the addition of methylb-cyclodextrin released monomeric Ab molecules. Nanogels composed of amino-group-modified CHP (CHPNH 2 ) with positive charges under physiological conditions had a greater inhibitory effect than CHP-nanogels, suggesting the importance of electrostatic interactions between CHPNH 2 and Ab for inhibiting the formation of fibrils. In addition, CHPNH 2 nanogels protected PC12 cells from Ab toxicity.

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Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-β aggregation

Cited by 127 publications

References 26 publications

Peroxidase Activity of Cyclooxygenase-2 (COX-2) Cross-links β-Amyloid (Aβ) and Generates Aβ-COX-2 Hetero-oligomers That Are Increased in Alzheimer's Disease

Peroxidase Activity of Cyclooxygenase-2 (COX-2) Cross-links β-Amyloid (Aβ) and Generates Aβ-COX-2 Hetero-oligomers That Are Increased in Alzheimer's Disease

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

Inhibition of the formation of amyloid β‐protein fibrils using biocompatible nanogels as artificial chaperones

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