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The Journal of Neuroscience, December 1, 2000, 20(23):8745-8749
Insulysin Hydrolyzes Amyloid  Peptides to Products That Are
Neither Neurotoxic Nor Deposit on Amyloid Plaques
Atish
Mukherjee1,
Eun-suk
Song1,
Muthoni
Kihiko-Ehmann2,
Jack P.
Goodman Jr3,
Jan St.
Pyrek3,
Steven
Estus2, and
Louis B.
Hersh1
1 Department of Biochemistry, 2 Department
of Physiology and Sanders-Brown Center on Aging, and 3 Mass
Spectrometry Facility, University of Kentucky, Lexington, Kentucky
40536-0298
Insulysin (EC. 3.4.22.11) has been implicated in the clearance of
 amyloid peptides through hydrolytic cleavage. To further study the
action of insulysin on A peptides recombinant rat insulysin was
used. Cleavage of both A1-40 and A1-42
by the recombinant enzyme was shown to initially occur at the
His13-His14,
His14-Gln15, and
Phe19-Phe20 bonds. This was
followed by a slower cleavage at the
Lys28-Gly29,
Val18-Phe19, and
Phe20-Ala21 positions. None of
the products appeared to be further metabolized by insulysin. Using a
rat cortical cell system, the action of insulysin on
A1-40 and A1-42 was shown to eliminate the neurotoxic effects of these peptides. Insulysin was further shown
to prevent the deposition of A1-40 onto a synthetic amyloid. Taken together these results suggest that the use of insulysin
to hydrolyze A peptides represents an alternative gene therapeutic
approach to the treatment of Alzheimer's disease.
Key words:
amyloid peptide metabolism; metallopeptidase; insulysin; A neurotoxicity; A deposition; A cleavage
Copyright © 2000 Society for Neuroscience 0270-6474/00/20238745-05$05.00/0
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