HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Effectiveness of Alzheimer Animal Models for Drug Testing Questioned

The increased A42/A40 ratio of PS1-Exon9 is due to the S290C mutation and lack of endoproteolytic cleavage.

The aberrant production and accumulation of amyloid -peptides (A) is a hallmark of Alzheimer disease. Thus, many disease-modifying therapies aim to block the production and increase the clearance of these plaques. Because A peptides are produced via cleavage of the amyloid precursor protein by - and -secretase, these proteases are prime drug targets. Recently, several nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, were shown to lower production of the highly amyloidogenic A42 peptide. Several studies indicate that NSAIDs act by modulating -secretase activity. This hypothesis is supported by the fact that mutations in the presenilin-1 subunit of -secretase change the response to NSAIDs.

In this Paper of the Week, Eva Czirr and colleagues explored the causes of the reduced NSAID response in the presenilin-1-Exon9 mutation. The mutation, which increases the A42/A40 ratio, results in a point mutation (S290C), a deletion (291–319), and lack of endoproteolytic cleavage. Czirr et al. showed that the point mutation and lack of endoproteolytic cleavage force a conformational change in the protein that results in the increased A42/A40 ratio and that the mutant's lack of endoproteolytic cleavage produces the diminished NSAID response. The authors also discovered that a diminished response to NSAIDs is common among aggressive presenilin-1 mutations and that these mutations are also unresponsive to -secretase inhibitors of different structural classes. This suggests that some in vitro and in vivo models of Alzheimer disease harboring presenilin mutations may not accurately evaluate the potency and efficacy of -secretase modulators and inhibitors.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 24504–24513

[More Papers of the Week]