Geneeskundige Stichting Koningin Elisabeth ... - GSKE - FMRE

The role of presenilin-1 in the gamma-secretase cleavage of the amyloid precursor protein of Alzheimer's disease.
Octave JN, Essalmani R, Tasiaux B, Menager J, Czech C, Mercken L. J Biol Chem. 275 (2000) 1525-1528.
The most common causes of familial Alzheimer's disease are mutations in genes encoding
presenilins (PS) 1 and 2. These mutations alter APP processing and cause increased production
of the high amyloidogenic Aß 42. Moreover, PS1-deficient mice show decreased g-secretase
processing of APP. PS are hydrophobic proteins that cross 6-8 times the membrane of the endoplasmic
reticulum. A limited portion of PS undergoes endoproteolysis and the resulting N- and
C-terminal fragments are localized predominantly in the Golgi. Presenilins are homologous to
proteins involved in vesicle transport or in the Notch developmental pathway in the nematode
Caenorhabditis elegans, and PS1-deficient mice show developmental abnormalities consistent
with altered Notch signaling. Signaling through the receptor protein Notch requires ligand-induced
cleavage of Notch. The recent demonstration that PS1 deficiency reduces the proteolytic
release of the Notch intracellular domain indicates that PS1 regulates both APP processing and
Notch signaling by influencing protein cleavage events. Since PS1 is required for both release
of intracellular domain of Notch and γ-secretase cleavage of APP, it has been proposed that
PS1 acts by facilitating the activity of the protease involved or is the protease itself. Human
APP695 and PS1 were coexpressed in Sf9 insect cells, in which endogenous g-secretase activity
is not detected. In baculovirus infected Sf9 cells, PS1 undergoes endoproteolysis and interacts
with APP. However, PS1 does not cleave APP in Sf9 cells. In CHO cells, endocytosis of APP
is required for Aß secretion. Deletion of the cytoplasmic sequence of APP (APPDC) inhibits both
APP endocytosis and Aß production. When APP∆C and PS1 are coexpressed in CHO cells, Aß
is secreted without endocytosis of APP. Taken together, these results conclusively show that,
although PS1 does not cleave APP in Sf9 cells, PS1 allows the secretion of Aß without endocytosis
of APP by CHO cells.
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