Development of a brain-permeable peptide nanofiber that prevents aggregation of Alzheimer pathogenic proteins.

Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidß in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid ßby trapping amyloid ß onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.

Mechanism of the chaperone-like and antichaperone activities of amyloid fibrils of peptides from αA-crystallin.

The amyloid fibril of a fragment of the substrate binding site of αA-crystallin (αAC(71-88)) exhibited chaperone-like activity by suppressing the aggregation of alcohol dehydrogenase (ADH) and luciferase. By contrast, the amyloid fibril of the cytotoxic fragment of amyloid ß protein (Aß(25-35)) facilitated the aggregation of the same proteins. We have determined the zeta potential of the amyloid fibril by measuring their electrophoretic mobility to study the effects of the surface charge on the modulation of protein aggregation. The αAC(71-88) amyloid possesses a large negative zeta potential value which is unaffected by the binding of the negatively charged ADH, indicating that the αAC(71-88) amyloid is stable as a colloidal dispersion. By contrast, the Aß(25-35) amyloid possesses a low zeta potential value, which was significantly reduced with the binding of the negatively charged ADH. The canceling of the surface charge of the amyloid fibril upon substrate binding reduces colloidal stability and thereby facilitates protein aggregation. These results indicate that one of the key factors determining whether amyloid fibrils display chaperone-like or antichaperone activity is their electrostatic interaction with the substrate. The surface of the αAC(71-88) amyloid comprises a hydrophobic environment, and the chaperone-like activity of the αAC(71-88) amyloid is best explained by the reversible substrate binding driven by hydrophobic interactions. On the basis of these findings, we designed variants of amyloid fibrils of αAC(71-88) that prevent protein aggregation associated with neurodegenerative disorders.