Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloidprecursor protein by a disintegrin metalloprotease

Citation
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
ISSN journal
00278424 → ACNP
Volume
96
Issue
7
Year of publication
1999
Pages
3922 - 3927
Database
ISI
SICI code
0027-8424(19990330)96:7<3922:CARACO>2.0.ZU;2-W
Abstract
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.