Jun 142008
ResearchBlogging.orgOne of the best-known features of Alzheimer’s disease pathology is the formation of proteinaceous amyloid plaques in the brain. In Alzheimer’s disease these plaques are primarily formed by the amyloid-β peptide (Aβ) derived from the amyloid precursor protein (APP) by the action of β- and γ-secretase. The length of the Aβ peptide varies, but the 42-residue form (Aβ42) is more likely to form plaques and fibrils. Although it remains uncertain whether plaques are a cause of Alzheimer’s disease symptoms, or merely an effect of some underlying derangement, finding some way to prevent or reduce plaque formation is a major goal in the field. This week in Nature, a team of researchers from institutions all over the US and Europe show that non-steroidal anti-inflammatory drugs (NSAIDs) may be able to accomplish these goals by binding to APP and Aβ directly.

Previous research from the Koo lab indicated that some NSAIDs specifically reduced the production of the amyloidogenic Aβ42 fragment (1) both in cultured cells and in a mouse model of the disease. APP was still processed into peptides, but these were shorter and less likely to form amyloid plaques than Aβ42. Significantly, the cleavage of other γ-secretase targets was not affected, meaning that side-effects of NSAID treatment might be minimal. Although NSAIDs were expected to ameliorate Alzheimer’s symptoms by reducing inflammation, Weggen et al. found that the beneficial effects were not the result of cyclooxygenase inhibition. In a follow-up paper (2), Weggen et al. used experiments on cultured cells to show that the drugs were directly modulating γ-secretase activity. These experiments also showed that mutations to presenilin-1, a core component of the γ-secretase complex, could either increase or decrease the effect of NSAIDs, suggesting that it was the protein directly affected by these drugs.

Kukar et al. set out to test this hypothesis using photaffinity labeling. They took a few compounds known to alter Aβ42 levels and added a functional group that would react with a protein in the presence of UV light. These covalently-labeled proteins could then be detected, and this would serve as a relatively easy way to determine which component of the γ-secretase complex was actually binding NSAIDs. Like many cleverly-designed experiments, this failed in an interesting way: no known components of the γ-secretase complex were labeled. Fortunately, the researchers realized that there was another component to the complex they hadn’t tested yet: the substrate.

It turned out that the NSAIDs could label a 99-residue fragment of APP. Moreover, this labeling was reduced by other γ-secretase modulators (GSMs) and unaffected by non-GSM NSAIDs. Using a series of progressively shorter constructs, Kukar et al. localized the binding activity of GSMs to residues 28-36 of amyloid-β.

This on its own is a very useful finding because it provides a target for refinement of these compounds. Knowing where and to what protein a possible drug binds makes it easier to develop assays to test new potential drugs, as well as enabling structure-based design. However, the authors took the next step and asked whether these drugs, because they bind to a region of APP known to be involved in the formation of amyloid plaques, might inhibit plaque formation directly. In cultured cells, they found that treatment with certain substrate-targeting GSMs decreased the formation of Aβ dimers and trimers even under conditions where the overall concentration of Aβ42 was not altered.

This suggests that these GSMs may be able to fight the buildup of amyloid plaques in two ways. By altering where γ-secretase cleaves APP, they reduce the concentration of Aβ42. Moreover, by interfering with Aβ oligomerization they fight the formation of plaques directly. With luck, further work in medicinal chemistry will arrive at compounds that enhance both these activities. The development of compounds that significantly reduce or prevent the formation of amyloid plaques will be a great step forward for Alzheimer’s research. Even if such drugs do not prove to be a cure, a clear indication that plaques don’t cause Alzheimer’s would be a critical insight.

I want to emphasize that although these results are quite promising, they do not prove the efficacy of NSAIDs in ameliorating actual Alzheimer’s symptoms. Transforming these findings into a cure or even an effective treatment will require a great deal of additional research, if it is even possible. You should not attempt to treat Alzheimer’s with NSAIDs, or begin a regimen of NSAIDs or any other kind of drug or supplement, unless you have first discussed the possible risks and benefits with your doctor. And no, Minnesota, I do not mean a naturopath.

1. Weggen, S., Eriksen, J.L., Das, P., Sagi, S.A., Wang, R., Pietrzik, C.U., Findlay, K.A., Smith, T.E., Murphy, M.P., Bulter, T., Kang, D.E., Marquez-Sterling, N., Golde, T.E., Koo, E.H. (2001). A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature, 414(6860), 212-216. DOI: 10.1038/35102591

2. Weggen, S. (2003). Evidence That Nonsteroidal Anti-inflammatory Drugs Decrease Amyloid β42 Production by Direct Modulation of γ-Secretase Activity. Journal of Biological Chemistry, 278(34), 31831-31837. DOI: 10.1074/jbc.M303592200 OPEN ACCESS

3. Kukar, T.L., Ladd, T.B., Bann, M.A., Fraering, P.C., Narlawar, R., Maharvi, G.M., Healy, B., Chapman, R., Welzel, A.T., Price, R.W., Moore, B., Rangachari, V., Cusack, B., Eriksen, J., Jansen-West, K., Verbeeck, C., Yager, D., Eckman, C., Ye, W., Sagi, S., Cottrell, B.A., Torpey, J., Rosenberry, T.L., Fauq, A., Wolfe, M.S., Schmidt, B., Walsh, D.M., Koo, E.H., Golde, T.E. (2008). Substrate-targeting γ-secretase modulators. Nature, 453(7197), 925-929. DOI: 10.1038/nature07055