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Accumulation of neurotoxic amyloid-beta is a major hallmark of
Alzheimer’s disease. Formation of amyloid-beta is catalysed by
gamma-secretase, a protease with numerous substrates. Little is known
about the molecular mechanisms that confer substrate specificity
on this potentially promiscuous enzyme. Knowledge of the
mechanisms underlying its selectivity is critical for the development
of clinically effective gamma-secretase inhibitors that can reduce
amyloid-beta formation without impairing cleavage of other gamma-secretase
substrates, especially Notch, which is essential for normal biological
functions. Here we report the discovery of a novel gamma-secretase
activating protein (GSAP) that drastically and selectively increases
amyloid-beta production through a mechanism involving its interactions
with both gamma-secretase and its substrate, the amyloid precursor
protein carboxy-terminal fragment (APP-CTF). GSAP does not
interact with Notch, nor does it affect its cleavage. Recombinant
GSAP stimulates amyloid-beta production in vitro. Reducing GSAP
concentrations in cell lines decreases amyloid-beta concentrations.
Knockdown of GSAP in a mouse model of Alzheimer’s disease
reduces levels of amyloid-b and plaque development. GSAP represents
a type of gamma-secretase regulator that directs enzyme specificity by
interacting with a specific substrate.We demonstrate that imatinib,
an anticancer drug previously found to inhibit amyloid-beta formation
without affecting Notch cleavage, achieves its amyloid-beta-lowering
effect by preventing GSAP interaction with the gamma-secretase substrate,
APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic
target without affecting other key functions of gamma-secretase.

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