S. Lammich et al., Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloidprecursor protein by a disintegrin metalloprotease, P NAS US, 96(7), 1999, pp. 3922-3927
Citations number
49
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Amyloid beta peptide (A beta), the principal proteinaceous component of amy
loid plaques in brains of Alzheimer's disease patients, is derived by prote
olytic cleavage of the amyloid precursor protein (APP). Proteolytic cleavag
e of APP by a putative alpha-secretase within the A beta sequence precludes
the formation of the amyloidogenic peptides and leads to the release of so
luble APPs alpha into the medium. By overexpression of a disintegrin and me
talloprotease (ADAM), classified as ADAM 10, in HEK 293 cells, basal and pr
otein kinase C-stimulated alpha-secretase activity was increased severalfol
d. The proteolytically activated form of ADAM 10 was localized by cell surf
ace biotinylation in the plasma membrane, but the majority of the proenzyme
was found in the Golgi. These results support the view that APP is cleaved
both at the cell surface and along the secretory pathway. Endogenous alpha
-secretase activity was inhibited by a dominant negative form of ADAM 10 wi
th a point mutation in the zinc binding site. Studies with purified ADAM 10
and A beta fragments confirm the correct alpha-secretase cleavage site and
demonstrate a dependence on the substrate's conformation. Our results prov
ide evidence that ADAM 10 has alpha-secretase activity and many properties
expected for the proteolytic processing of APP, Increases of its expression
and activity might be beneficial for the treatment of Alzheimer's disease.