The findings are significant for three main reasons:

First: They provide strong evidence that NSAIDs bind to and modulate γ-secretase function in the brain. This extends findings from Dr. Koo's and my laboratories (Weggen et al., Eriksen et al. references in paper), Greg Cole's laboratory (Lim et al.), Dave Morgan's Lab (Jantzen et al.), and Neill Kowall's laboratory (Yan et al.) that show that some NSAIDs 1) reduce Aβ deposition in transgenic mice, 2) acutely lower Aβ42 levels in the brain, and 3) appear to target γ-secretase.

Second: What this study appears to show is that despite concentrations in the brain that are well below the levels needed to lower Aβ42 in cell culture (Eriksen et al.), certain NSAIDs appear capable of altering PS conformation in the brain. This would support the notion that NSAIDs are concentrated in the compartments in the brain where γ-secretase resides. This provides direct evidence that certain NSIADs could lower Aβ42 in the brain.

Third: They utilize the FLIM technique to show that the drugs bind and induce a conformational change in...  Read more

The findings are significant for three main reasons:

First: They provide strong evidence that NSAIDs bind to and modulate γ-secretase function in the brain. This extends findings from Dr. Koo's and my laboratories (Weggen et al., Eriksen et al. references in paper), Greg Cole's laboratory (Lim et al.), Dave Morgan's Lab (Jantzen et al.), and Neill Kowall's laboratory (Yan et al.) that show that some NSAIDs 1) reduce Aβ deposition in transgenic mice, 2) acutely lower Aβ42 levels in the brain, and 3) appear to target γ-secretase.

Second: What this study appears to show is that despite concentrations in the brain that are well below the levels needed to lower Aβ42 in cell culture (Eriksen et al.), certain NSAIDs appear capable of altering PS conformation in the brain. This would support the notion that NSAIDs are concentrated in the compartments in the brain where γ-secretase resides. This provides direct evidence that certain NSIADs could lower Aβ42 in the brain.

Third: They utilize the FLIM technique to show that the drugs bind and induce a conformational change in γ-secretase. This is a really cool demonstration of how imaging techniques can be used to view molecular alterations.

The notion that this technique can be used for screening is not unreasonable. However, one would want to show that it actually works with a much larger number of compounds. In this case, we can directly look for compounds that lower Aβ42 so in this instance there are more direct alternatives. However, there may be cases where it would be preferable to analyze structural changes by this technique (for example when one is trying to inhibit a protein-protein interaction)….

References:
Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001 Nov 8;414(6860):212-6. Abstract

Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci. 2000 Aug 1;20(15):5709-14. Abstract

Jantzen PT, Connor KE, DiCarlo G, Wenk GL, Wallace JL, Rojiani AM, Coppola D, Morgan D, Gordon MN. Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci. 2002 Mar 15;22(6):2246-54. Abstract

Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci. 2003 Aug 20;23(20):7504-9. Abstract

Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest. 2003 Aug;112(3):440-9. Abstract

Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Ozols V, Fauq A, Golde TE, Koo EH. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem. 2003 Aug 22;278(34):31831-7. Epub 2003 Jun 12. Abstract

View all comments by Todd E. Golde

Allosteric modulation of γ-secretase activity offers a new avenue for specific inhibition of Aβ42 production
Using fluorescence lifetime imaging (FLIM), the authors demonstrate that certain NSAIDs known to specifically reduce Aβ42 levels without altering total Aβ induce a structural rearrangement in the catalytic center of γ-secretase (presenilin, PS). Binding of these compounds also alters the interaction between PS1 and APP, thus suggesting that the allosteric rearrangement of PS allows APP to be cleaved at an alternate site. These findings are supported by recent enzyme kinetic studies that demonstrate that sulindac sulfide and R-flurbiprofen act as allosteric modulators of γ-secretase (Beher et al., 2004).

Identification of the allosteric site at which NSAIDs bind should facilitate the generation of highly specific inhibitors of Aβ42 generation and thus minimize unwanted inhibition of the γ-secretase processing of other important substrates.

Reference:
Beher D, Clarke EE, Wrigley JD, Martin AC, Nadin A, Churcher I, Shearman MS. Selected non-steroidal...  Read more

Allosteric modulation of γ-secretase activity offers a new avenue for specific inhibition of Aβ42 production
Using fluorescence lifetime imaging (FLIM), the authors demonstrate that certain NSAIDs known to specifically reduce Aβ42 levels without altering total Aβ induce a structural rearrangement in the catalytic center of γ-secretase (presenilin, PS). Binding of these compounds also alters the interaction between PS1 and APP, thus suggesting that the allosteric rearrangement of PS allows APP to be cleaved at an alternate site. These findings are supported by recent enzyme kinetic studies that demonstrate that sulindac sulfide and R-flurbiprofen act as allosteric modulators of γ-secretase (Beher et al., 2004).

Identification of the allosteric site at which NSAIDs bind should facilitate the generation of highly specific inhibitors of Aβ42 generation and thus minimize unwanted inhibition of the γ-secretase processing of other important substrates.

Reference:
Beher D, Clarke EE, Wrigley JD, Martin AC, Nadin A, Churcher I, Shearman MS. Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site-evidence for an allosteric mechanism. J Biol Chem. 2004 Aug 10 [Epub ahead of print] Abstract

View all comments by Dominic Walsh

I agree that this is a very impressive attempt to use the power of energy transfer techniques to study the effects of NSAIDs on the organization of the presenilin/γ-secretase complex. I am concerned that the fluorophores used to measure lifetimes could conceivably be two antibody lengths away from the target antigens of the presenilin molecules, since each fluorophore was attached to secondary antibodies that were then bound to primary anti-PS1 antibodies. Since there were differences in response as a result of exposure to specific NSAIDs, something interesting is going on, but the changes in PSI conformation proposed by the authors are only one of many possible explanations.

View all comments by Vincent Marchesi