Ketan Desai

Myriad Options on Alzheimers Disease

To Ksaales:

Gamma secretase is not the only MOA of NSAIDS in AD (see below from an article published in NEJM). That is why I stand by my statement that "this study gives hints on the possible outcome".

The neuropathologic features of Alzheimer's disease include the accumulation of microglia around plaques, a local cytokine-mediated acute-phase response, and activation of the complement cascade (1,2). This inflammatory response may damage neurons and exacerbate the pathologic processes underlying the disease (3). Nonsteroidal antiinflammatory drugs (NSAIDs) may influence this inflammatory response by inhibiting cyclooxygenase-1 and cyclooxygenase-2 and by activating the peroxisome proliferator (PPAR) nuclear transcription factor (4,5,6). In addition, cyclooxygenase-mediate... oxidation is important in the calcium-dependent glutamate-signaling pathway that involves N-methyl-D-aspartate. In this way, NSAIDs may be able to protect neurons directly by reducing cellular responses to glutamate (7).

1. Aisen PS. Inflammation and Alzheimer's disease: mechanisms and therapeutic strategies. Gerontology 1997;43:143-149.
2. Aisen PS. Inflammation and Alzheimer disease. Mol Chem Neuropathol 1996;28:83-88.
3. McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995;21:195-218.
4. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1997;272:3406-3410.
5. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998;391:79-82.
6. Leveugle B, Fillit H. Proteoglycans and the acute-phase response in Alzheimer's disease brain. Mol Neurobiol 1994;9:25-32.
7. Breitner JC. Inflammatory processes and antiinflammatory drugs in Alzheimer's disease: a current appraisal. Neurobiol Aging 1996;17:789-794.