ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2011
Inhibitors of γ-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Engineered APP C-terminus Alters Its Native Transcript Dynamics in Differentiated SH-SY5Y-Derived Neurons.Molecular neurobiology · 2026Article
- Fully defined NGN2 neuron protocol reveals diverse signatures of neuronal maturation.Cell reports methods · 2024Article
- APP accumulates with presynaptic proteins around amyloid plaques: A role for presynaptic mechanisms in Alzheimer's disease?Alzheimer's & dementia : the journal of the Alzheimer's Association · 2022Article
- Article
- PS1 FAD mutants decrease ephrinB2-regulated angiogenic functions, ischemia-induced brain neovascularization and neuronal survival.Molecular psychiatry · 2021Article
- Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex.Scientific reports · 2021Article
- Article
- Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity.Nature communications · 2018Article
- Presenilin1/γ-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- Mechanisms that synergistically regulate η-secretase processing of APP and Aη-α protein levels: relevance to pathogenesis and treatment of Alzheimer's disease.Discovery medicine · 2017Article
- Presenilin 1 is necessary for neuronal, but not glial, EGFR expression and neuroprotection via γ-secretase-independent transcriptional mechanisms.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2015Article
- The dynamic conformational landscape of gamma-secretase.Journal of cell science · 2015Article
- Structural biology of presenilin 1 complexes.Molecular neurodegeneration · 2014Review
- Cyclopamine modulates γ-secretase-mediated cleavage of amyloid precursor protein by altering its subcellular trafficking and lysosomal degradation.The Journal of biological chemistry · 2014Article
- Evidence of a novel mechanism for partial γ-secretase inhibition induced paradoxical increase in secreted amyloid β protein.PloS one · 2014Article
- Neuropathological and biochemical assessments of an Alzheimer's disease patient treated with the γ-secretase inhibitor semagacestat.American journal of neurodegenerative disease · 2014Article
- Cell signaling abnormalities may drive neurodegeneration in familial Alzheimer disease.Neurochemical research · 2014Review
- Presenilins regulate neurotrypsin gene expression and neurotrypsin-dependent agrin cleavage via cyclic AMP response element-binding protein (CREB) modulation.The Journal of biological chemistry · 2013Article
- Presenilin-1/γ-secretase controls glutamate release, tyrosine phosphorylation, and surface expression of N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B.The Journal of biological chemistry · 2013Article
- Interplay between α-, β-, and γ-secretases determines biphasic amyloid-β protein level in the presence of a γ-secretase inhibitor.The Journal of biological chemistry · 2013Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
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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