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.