Insulysin hydrolyzes amyloid beta peptides to products that are neither neurotoxic nor deposit on amyloid plaques

Insulysin (EC. 3.4.22.11) has been implicated in the clearance of beta amyl oid peptides through hydrolytic cleavage. To further study the action of in sulysin on A beta peptides recombinant rat insulysin was used. Cleavage of both A beta (1-40) and A beta (1-42) by the recombinant enzyme was shown to initially occur at the His(13)-His(14), His(14)-Gln(15), and Phe(19)-Phe(2 0) bonds. This was followed by a slower cleavage at the Lys(28)-Gly(29),Val (18)-Phe(19), and Phe(20)-Ala(21) positions. None of the products appeared to be further metabolized by insulysin. Using a rat cortical cell system, t he action of insulysin on A beta (1-40) and A beta (1-42) was shown to elim inate the neurotoxic effects of these peptides. Insulysin was further shown to prevent the deposition of A beta (1-40) onto a synthetic amyloid. Taken together these results suggest that the use of insulysin to hydrolyze A be ta peptides represents an alternative gene therapeutic approach to the trea tment of Alzheimer's disease.