A synthetic nonapeptide, JAL-TA9, inhibits neuronal cytotoxicity caused by Aβ25-35 aggregation with proteolytic activity.

Abstract

Due to the growing number of Alzheimer's disease (AD) patients, new drugs are urgently required. A synthetic nonapeptide, JAL-TA9 (YKGSGFRMI), derived from Transducer of ErbB-2.1 (Tob1) protein, cleaves amyloid β (Aβ) 42 with serine protease-like activity. Aβ25-35 was chosen because it is the shortest fragment that forms fibrils and is cytotoxic. Aβ25-35 has been used to create AD model mice, and it appears to be an attractive target for AD therapeutics. Using Thioflavin-T assays, the fluorescence intensity of the reaction of Aβ25-35 and JAL-TA9 was lower than that of Aβ25-35 without JAL-TA9, and the same result was obtained with aggregated Aβ25-35. These data showed that JAL-TA9 inhibits aggregation of Aβ25-35 and dissolves its aggregates. Furthermore, electron microscopy showed that amyloid fibrils of both Aβ25-35 and aggregated Aβ25-35 are reduced in the presence of JAL-TA9. The proteolytic activity of JAL-TA9 against Aβ25-35 was evaluated using HPLC and mass spectrometry. These data showed that JAL-TA9 cleaves both soluble and aggregated forms of Aβ25-35. JAL-TA9 inhibits neuronal cytotoxicity caused by Aβ25-35 aggregation by cleaving Aβ25-35 and its aggregated form. These results suggest that JAL-TA9 is a promising candidate for developing novel drugs against AD.