Neurotoxicity of Alzheimer's disease A[beta] peptides is induced by small changes in the A[beta]42 to A[beta]40 ratio

• Published in: The EMBO journal 2010-10, Vol.29 (19), p.3408
• Main Authors: Kuperstein, Inna, Broersen, Kerensa, Benilova, Iryna, Rozenski, Jef, Jonckheere, Wim, Debulpaep, Maja, Vandersteen, Annelies, Segers-nolten, Ine, Van Der Werf, Kees, Subramaniam, Vinod, Braeken, Dries, Callewaert, Geert, Bartic, Carmen, D'hooge, Rudi, Martins, Ivo Cristiano, Rousseau, Frederic, Schymkowitz, Joost, De Strooper, Bart
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Biological properties; Neurotoxicity; Peptides
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2010.211

One of the most challenging issues in Alzheimer's Disease (AD) research is the unresolved nature of the Ab-peptide conformation(s) that exert neurotoxicity. Our current work shows that Ab-associated toxicity is a dynamic property and that a critical equilibrium between the two major Ab species, Ab40 and Ab42, exists, which determines the rate of appearance of these toxic properties as assessed in neuronal cell culture and in brains of animals in vivo. Our study design has taken this dynamic behaviour into account by indicating the time of aggregation of the peptides used in each experiment. We found that relative high concentrations of Ab are needed to induce brillization and toxic-oligomer conformation. Although this might seem an articial situation, one should realize that by increasing the Ab concentrations, processes which otherwise take decades become accelerated to the extent that they can be studied in laboratory conditions. Most importantly, such high concentrations of Ab might actually be even quite relevant for what happens in vivo. A recent publication suggested indeed that intracellular compartments accumulate Ab at high mM concentrations, which could create the conditions for the local formation of the elusive toxic conformations of Ab peptides (Hu et al, 2009).