Interactions between APP secretases and inflammatory mediators.
There is now a large body of evidence linking inflammation to Alzheimer's disease (AD). This association manifests itself neuropathologically in the presence of activated microglia and astrocytes around neuritic plaques and increased levels of inflammatory mediators in the brains of AD patients. It is considered that amyloid-beta peptide (Abeta), which is derived from the processing of the longer amyloid precursor protein (APP), could be the most important stimulator of this response, and therefore determining the role of the different secretases involved in its generation is essential for a better understanding of the regulation of inflammation in AD. The finding that certain non-steroidal anti-inflammatory drugs (NSAIDs) can affect the processing of APP by inhibiting beta- and gamma-secretases, together with recent revelations that these enzymes may be regulated by inflammation, suggest that they could be an interesting target for anti-inflammatory drugs. In this review we will discuss some of these issues and the role of the secretases in inflammation, independent of their effect on Abeta formation.
Sastre
Magdalena
M
Division of Neuroscience and Mental Health, Imperial College London, The Hammersmith Hospital, Du cane Road, London W12 0NN, UK. m.sastre@imperial.ac.uk
Walter
Jochen
J
Gentleman
Steve M
SM
D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001921:Brain / Q000201:enzymology / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology*; D008565:Membrane Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D050794:STAT1 Transcription Factor; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; C098339:ADAM9 protein, human; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein