OPEN IN READ APP
JOURNAL ARTICLE

Development of a proteolytically stable retro-inverso peptide inhibitor of beta-amyloid oligomerization as a potential novel treatment for Alzheimer's disease

Mark Taylor, Susan Moore, Jennifer Mayes, Edward Parkin, Marten Beeg, Mara Canovi, Marco Gobbi, David M A Mann, David Allsop
Biochemistry 2010 April 20, 49 (15): 3261-72
20230062
The formation of beta-amyloid (Abeta) deposits in the brain is likely to be a seminal step in the development of Alzheimer's disease. Recent studies support the hypothesis that Abeta soluble oligomers are toxic to cells and have potent effects on memory and learning. Inhibiting the early stages of Abeta aggregation could, therefore, provide a novel approach to treating the underlying cause of AD. We have designed a retro-inverso peptide (RI-OR2, H(2)N-r<--G<--k<--l<--v<--f<--f<--G<--r-Ac), based on a previously described inhibitor of Abeta oligomer formation (OR2, H(2)N-R-G-K-L-V-F-F-G-R-NH(2)). Unlike OR2, RI-OR2 was highly stable to proteolysis and completely resisted breakdown in human plasma and brain extracts. RI-OR2 blocked the formation of Abeta oligomers and fibrils from extensively deseeded preparations of Abeta(1-40) and Abeta(1-42), as assessed by thioflavin T binding, an immunoassay method for Abeta oligomers, SDS-PAGE separation of stable oligomers, and atomic force microscopy, and was more effective against Abeta(1-42) than Abeta(1-40). In surface plasmon resonance experiments, RI-OR2 was shown to bind to immobilized Abeta(1-42) monomers and fibrils, with an apparent K(d) of 9-12 muM, and also acted as an inhibitor of Abeta(1-42) fibril extension. In two different cell toxicity assays, RI-OR2 significantly reversed the toxicity of Abeta(1-42) toward cultured SH-SY5Y neuroblastoma cells. Thus, RI-OR2 represents a strong candidate for further development as a novel treatment for Alzheimer's disease.

Comments

You need to log in or sign up for an account to be able to comment.

No comments yet, be the first to post one!

Related Papers

Available on the App Store

Available on the Play Store
Remove bar
Read by QxMD icon Read
20230062
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"