Abstract
The formation of Aβ is directly controlled by the γ-secretase complex and its activator, γ-secretase activating protein (GSAP). GSAP derives from a C-terminal fragment of a larger precursor protein via a caspase-3 mediated cleavage. However, the mechanism regulating this process remains unknown. Here we provide in vitro experimental evidence that 5-Lipoxygenase (5LO) is as an endogenous regulator for GSAP formation, but not for other known γ-secretase modulators, by directly and specifically activating caspase-3. These results were confirmed in vivo by using transgenic mouse models of Alzheimer's disease in which 5LO level and activity were modulated genetically or pharmacologically. Taken together, our findings demonstrate that GSAP cleavage via caspase-3 is regulated and depend upon the availability of 5LO further establishing this protein as an attractive and viable therapeutic target for Alzheimer's disease.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alzheimer Disease / genetics*
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases / genetics*
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / genetics*
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Amyloid beta-Peptides / metabolism
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Animals
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Arachidonate 5-Lipoxygenase / genetics*
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Arachidonate 5-Lipoxygenase / metabolism
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Caspase 3 / genetics*
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Caspase 3 / metabolism
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Cell Line
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Disease Models, Animal
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Gene Expression Regulation
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Humans
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Lipoxygenase Inhibitors / pharmacology
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Mice
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Mice, Transgenic
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Neurons / metabolism
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Neurons / pathology
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Proteins / genetics*
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Proteins / metabolism
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Proteolysis
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction
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Transfection
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Transgenes
Substances
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Amyloid beta-Peptides
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Lipoxygenase Inhibitors
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Proteins
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Recombinant Proteins
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gamma-secretase activating protein, mouse
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Arachidonate 5-Lipoxygenase
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Amyloid Precursor Protein Secretases
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Casp3 protein, mouse
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Caspase 3