Insulysin hydrolyzes amyloid β 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 β amyloid peptides through hydrolytic cleavage. To further study the action of insulysin on Aβ peptides recombinant rat insulysin was used. Cleavage of both Aβ(1-40) and Aβ(1-42) by the recombinant enzyme was shown to initially occur at the His¹³-His(14), His(14)-Gln(15), and Phe(19)-Phe(20) 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, the action of insulysin on Aβ(1-40) and Aβ(1-42) was shown to eliminate the neurotoxic effects of these peptides. Insulysin was further shown to prevent the deposition of Aβ(1-40) onto a synthetic amyloid. Taken together these results suggest that the use of insulysin to hydrolyze Aβ peptides represents an alternative gene therapeutic approach to the treatment of Alzheimer's disease.