Nonsteroidal anti-inflammatory drugs can lower amyloidogenic A42by inhibiting Rho.
In addition to their role in preventing pain and inflammation, some nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac sulphide, ibuprofen and indomethacin, have the unexpected benefit of reducing the risk of developing Alzheimer's disease. But why only certain NSAIDs seem to protect against Alzheimer's disease is a perplexing question. According to a recent study published in Science, the answer, it seems, depends on the interaction of these drugs with the small GTP-binding protein (G protein) Rho, and Rho's influence on what forms of amyloid- (A) are produced.
The A peptide is generated when the amyloid precursor protein (APP) is cut by -secretase, and because -secretase can cut APP at various points, A peptides of different lengths are produced (38, 40 or 42 amino acids). But it is the 42-amino-acid variant, A42, that is predominant in the brain plaques that are a pathogenic hallmark of Alzheimer's disease. Previous research had suggested that certain NSAIDs protect against Alzheimer's disease by reducing the amount of A42, through an unknown mechanism that was independent of their anti-inflammatory activity. As NSAIDs have also been shown to inhibit signalling by the small G protein Ras, Zhou and colleagues decided to investigate the effects of small G-protein signalling on the regulation of A42.
They first showed that increasing the activity of small G proteins in cultured cells selectively increased the concentration of A42 over total A, an increase that could be completely blocked by the NSAIDs sulindac sulphide and ibuprofen. This activity was pinpointed to Rho, which is involved in numerous cellular processes, including cell migration and survival, transcriptional regulation and vesicle transport.
In cultured cells, inhibition of the Rho effector Rho-associated kinase (Rock) by Y-27632 reduced A42 levels in a concentration-dependent manner, and was also shown to block Rho-mediated increases in A42, suggesting that Rock acts downstream of Rho in the regulation of A42. Furthermore, treating a transgenic mouse model of Alzheimer's disease with Y-27632 reduced brain levels of A42 and the ratio of A42 to total A. So, the Rho–Rock pathway has an important role in regulating A42 levels, both in vitro and in vivo.
The authors then showed that the NSAIDs sulindac sulphide, ibuprofen and indomethacin inhibited Rho activity. By contrast, the NSAIDs naproxen, meloxicam, SC-560 and piroxicam, which are ineffective at lowering levels of A42, showed little effect on the activity of Rho. The A42-lowering NSAIDs also increased the levels of A38, and the researchers showed that altering the activity of Rho and Rock also affects both A42 and A38 levels. So, they suggest that Rho–Rock signalling modulates the cleavage specificity of -secretase, and that NSAIDs therefore also alter the cutting activity of -secretase through their interaction with Rho.
The side effects of NSAIDs, which include gastrointestinal and renal toxicity, might preclude their long-term use to prevent Alzheimer's disease, but perhaps isolating the Rho-inhibitory activity of these drugs could lead to a novel approach to treat the disease.
Clare Ellis
References
Zhou, Y. et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic A42 by inhibiting Rho. Science302, 1215–1217 (2003) | Article | PubMed |
Weggen, S. et al. A subset of NSAIDs lower amyloidogenic A42 independently of cyclooxygenase activity. Nature414, 212–216 (2001) | Article | PubMed |
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