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Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site
γ-Secretase is an aspartyl intramembrane protease that cleaves the amyloid precursor protein (APP) involved in Alzheimer’s disease pathology and...
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Effects of presenilin-1 familial Alzheimer’s disease mutations on γ-secretase activation for cleavage of amyloid precursor protein
Presenilin-1 (PS1) is the catalytic subunit of γ-secretase which cleaves within the transmembrane domain of over 150 peptide substrates. Dominant...
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Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase
Intramembrane proteases play a pivotal role in biology and medicine, but how these proteases decode cleavability of a substrate transmembrane (TM)...
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A thermodynamic investigation of amyloid precursor protein processing by human γ-secretase
Human γ-secretase cleaves the transmembrane domains (TMDs) of amyloid precursor protein (APP) into pathologically relevant amyloid-β peptides (Aβs)....
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Turning the tide on Alzheimer’s disease: modulation of γ-secretase
Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. Amyloid-beta (Aβ) plaques are integral to the “amyloid hypothesis,”...
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Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complex
Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and...
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Targeting notch signaling pathway in breast cancer stem cells through drug repurposing approach
Breast cancer is recognized globally as one of the leading causes of malignant morbidity. It is a heterogeneous disease that accounts for 30 percent...
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Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol
Amyloid β is considered a key player in the development and progression of Alzheimer’s disease (AD). Many studies investigating the effect of statins...
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The amyloid precursor protein and its derived fragments concomitantly contribute to the alterations of mitochondrial transport machinery in Alzheimer’s disease
Mitochondria dysfunctions and mitophagy failure have been associated with several Alzheimer’s disease (AD) related molecular actors including amyloid...
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A tailored tetravalent peptide displays dual functions to inhibit amyloid β production and aggregation
Inhibition of amyloid-β peptide (Aβ) accumulation in the brain is a promising approach for treatment of Alzheimer’s disease (AD). Aβ is produced by...
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Adherens junctions organize size-selective proteolytic hotspots critical for Notch signalling
Adherens junctions (AJs) create spatially, chemically and mechanically discrete microdomains at cellular interfaces. Here, using a mechanogenetic...
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Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion
Jagged1 (JAG1) is a Notch ligand that correlates with tumor progression. Not limited to its function as a ligand, JAG1 can be cleaved, and its...
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A novel mouse model for N-terminal truncated Aβ2-x generation through meprin β overexpression in astrocytes
Neurotoxic amyloid-β (Aβ) peptides cause neurodegeneration in Alzheimer’s disease (AD) patients’ brains. They are released upon proteolytic...
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The transmembrane domain of Frey1 harbors a transplantable inhibitory motif for intramembrane proteases
Although aspartic intramembrane-cleaving proteases (I-CLIPs) are crucial switches of multiple signaling pathways and involved in several devastating...
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Thermal proteome profiling unveils protein targets of deoxycholic acid in living neuronal cells
Bile acids, synthesized in the liver and modified by the gut microbiota, play vital roles in various physiological processes. The dysregulation of...
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Simple modeling of familial Alzheimer’s disease using human pluripotent stem cell-derived cerebral organoid technology
BackgroundCerebral organoids (COs) are the most advanced in vitro models that resemble the human brain. The use of COs as a model for Alzheimer’s...
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Notch pathway is required for protection against heat stress in spermatogonial stem cells in medaka
Gamete production is a fundamental process for reproduction; however, exposure to stress, such as increased environmental temperature, can decrease...
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A delay in vesicle endocytosis by a C-terminal fragment of N-cadherin enhances Aβ synaptotoxicity
Synaptotoxic Aβ oligomers are thought to play a major role in the early pathology of Alzheimer´s disease (AD). However, the molecular mechanisms...
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Revisiting APP secretases: an overview on the holistic effects of retinoic acid receptor stimulation in APP processing
Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the accumulation of the β-amyloid peptide (Aβ) in the...
