The discovery of JAL-TA9 which cleaves amyloid-β with proteolytic activity

Abstract

Amyloid-β (Aβ) 42, one of the causes of Alzheimer's disease (AD), is produced by the cleavage of amyloid precursor protein (APP) by β- or γ-secretases. Since Aβ42 oligomers exhibit strong neurotoxicity, Aβ42 is predicted to be a potentially efficient target for drug therapies. Recently, we screened peptides that activate MMP7 using our peptide library and found that the synthetic peptide JAL-TA9 (YKGSGFRMI), which is derived from the BoxA region of Tob1 protein, showed proteolytic activity. It is generally accepted that an enzyme should be a large molecular protein consisting of more than thousands of amino acids. Thus, this is the first finding that a small synthetic peptide has protease activity, and we termed Catalytide as the general name of peptides with protease activity. In this study, we demonstrate the cleavage activity of JAL-TA9 not only against the authentic soluble form of Aβ42 but also against the solid type of Aβ42 in the central region. In addition, we demonstrated the cleavage activity using brain slices of AD patients. JAL-TA9 decreased the amount of accumulated Aβ42 in the brain of Alzheimer's patients. Taken together, JAL-TA9 is an attractive seed for the development of peptide drugs with a new strategy for Alzheimer's disease.