Inhibitors of γ-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates

Gael Barthet, Junichi Shioi, Zhiping Shao, Yimin Ren, Anastasios Georgakopoulos, Nikolaos K. Robakis
FASEB j.. 2011-05-19; 25(9): 2937-2946
DOI: 10.1096/fj.11-183806

PubMed
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Barthet G(1), Shioi J, Shao Z, Ren Y, Georgakopoulos A, Robakis NK.

Author information:
(1)Department of Psychiatry, Mt. Sinai School of Medicine, New York University, New York, NY 10029, USA.

γ-Secretase inhibitors (GSIs) are drugs used in research to inhibit production of
Aβ and in clinical trials to treat Alzheimer’s disease (AD). They inhibit
proteolytic activities of γ-secretase noncompetitively by unknown mechanisms.
Here, we used cortical neuronal cultures expressing endogenous levels of enzymes
and substrates to study the effects of GSIs on the structure and function of
γ-secretase. We show that GSIs stabilize the interactions between the C-terminal
fragment of presenilin (PS-CTF), the central component of the γ-secretase
complex, and its partners the APH-1/nicastrin and PS1-NTF/PEN-2 subcomplexes.
This stabilization dose-dependently correlates with inhibition of N-cadherin
cleavage, a process limited by enzyme availability. In contrast, production of
amyloid precursor protein (APP) intracellular domain (AICD) is insensitive to low
concentrations of GSIs and is limited by substrate availability. Interestingly,
APP is processed by both PS1- and PS2-containing γ-secretase complexes, while
N-cadherin and ephrinB1 are processed only by PS1-containing complexes.
Paradoxically, low concentrations of GSIs specifically increased the levels of Aβ
without affecting its catabolism, indicating increased Aβ production. Our data
reveal a mechanism of γ-secretase inhibition by GSIs and provide evidence that
distinct γ-secretase complexes process specific substrates. Furthermore, our
observations have implications for GSIs as therapeutics because processing of
functionally important substrates may be inhibited at lower concentrations than
Aβ.

 

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