C-terminal peptides coassemble into Aβ42 oligomers and protect neurons against Aβ42-induced neurotoxicity

Alzheimer's disease (AD) is an age-related disorder that threatens to become an epidemic as the world population ages. Neurotoxic oligomers of A beta 42 are believed to be the main cause of AD; therefore, disruption of A beta oligomerization is a promising approach for developing therapeutics for AD. Formation of A beta 42 oligomers is mediated by intermolecular interactions in which the C terminus plays a central role. We hypothesized that peptides derived from the C terminus of A beta 42 may get incorporated into oligomers of A beta 42, disrupt their structure, and thereby inhibit their toxicity. We tested this hypothesis using A beta fragments with the general formula A beta(x-42) (x = 28-39). A cell viability screen identified A beta(31-42) as the most potent inhibitor. In addition, the shortest peptide, A beta(39-42), also had high activity. Both A beta(31-42) and A beta(39-42) inhibited A beta-induced cell death and rescued disruption of synaptic activity by A beta 42 oligomers at micromolar concentrations. Biophysical characterization indicated that the action of these peptides likely involved stabilization of A beta 42 in nontoxic oligomers. Computer simulations suggested a mechanism by which the fragments coassembled with A beta 42 to form heterooligomers. Thus, A beta(31-42) and A beta(39-42) are leads for obtaining mechanism-based drugs for treatment of AD using a systematic structure-activity approach.