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Prostaglandin I2 accumulation in neuronal cells activates PKA/CREB (show CREB1 ELISA Kits) and JNK/c-Jun signaling pathways by phosphorylation, which results in APH-1alpha/1beta expression.
Thus, Leda-1/Pianp is constitutively processed by proprotein convertases, sheddases including MMPs and ADAM10 (show ADAM10 ELISA Kits)/17 and intramembrane protease gamma-secretase.
Abeta (show APP ELISA Kits) oligomers in the cerebrospinal fluid (CSF (show CSF2 ELISA Kits)) further promoted the expression of APH-1alpha/-1beta (by >2.5-fold), which enhances the gamma-cleavage of APP (show APP ELISA Kits) and Abeta (show APP ELISA Kits) deposition during AD progression
Upregulation of PS1 (show PSEN1 ELISA Kits)/gamma-secretase activity may be a risk factor for late onset sporadic Alzheimer's disease.
ficiency of beta-arrestin1 (show ARRB1 ELISA Kits) or inhibition of binding of beta-arrestin1 (show ARRB1 ELISA Kits) with APH-1 by small peptides reduced Abeta (show APP ELISA Kits) production without affecting Notch (show NOTCH1 ELISA Kits) processing
Pen-2 (show PSENEN ELISA Kits), as well as nicastrin (show NCSTN ELISA Kits) and Aph-1alpha, is dispensable for presenilin endoproteolysis
We propose a model that identifies critical TMDs of Aph-1 for associations with Nct (show NCSTN ELISA Kits) and PS for the stepwise assembly of gamma-secretase components.
Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates
presenilin 1 (PS1 (show PSEN1 ELISA Kits))-derived fragments, mature nicastrin (show NCSTN ELISA Kits), APH-1, and PEN-2 (show PSENEN ELISA Kits), associate with cholesterol-rich detergent insoluble membrane (DIM) domains of non-neuronal cells and neurons
Our findings establish that APH-1a is the major mammalian APH-1 homolog present in presenilin-dependent gamma-secretase complexes during embryogenesis.
Data show that presenilin 1 (PS1 (show PSEN1 ELISA Kits))/anterior-pharynx-defective protein 1 (Aph1b (show aph1b ELISA Kits)), presenilin 2 (PS2 (show PSEN2 ELISA Kits))/Aph1aL, PS2 (show PSEN2 ELISA Kits)/Aph1aS and PS2 (show PSEN2 ELISA Kits)/anterior pharynx defective 1 homolog B (Aph1b (show aph1b ELISA Kits)) gamma-secretase produced amyloid beta peptide (Abeta (show APP ELISA Kits)) with a higher Abeta42+Abeta43-to-Abeta40 (Abeta42(43)/Abeta40) ratio than the other gamma-secretases.
Data show that presenilin 1 (PS1 (show PSEN1 ELISA Kits))-containing gamma-secretase complexes were targeted to the plasma membrane, whereas presenilin 2 (PS2 (show PSEN2 ELISA Kits))-containing ones were addressed to the trans-Golgi network, to recycling endosomes.
No statistically significant difference was detected either in APOE (show APOE ELISA Kits) or APH-1a polymorphisms, not suggesting a strong susceptibility to the development of Alzheimer disease.
analysis of how the conformation of presenilin, Pen-2 (show PSENEN ELISA Kits), Aph-1, and nicastrin (show NCSTN ELISA Kits) affect the function and mechanism of gamma-secretase
We demonstrate that extending the transmembrane domain of the amyloid precursor protein (show APP ELISA Kits)-derived C99 substrate in proximity to the cytosolic face strongly influences gamma-secretase cleavage specificity.
The -980C/G polymorphism in APH-1A promoter confers risk of Alzheimer's disease
Coexpression of wild-type or S-palmitoylation-deficient APH1aL and nicastrin (show NCSTN ELISA Kits) leads to marked stabilization of transgenic presenilin 1 (show PSEN1 ELISA Kits) in the brains of double-transgenic mice.
Endogenous Aph-1a and its proteolytic fragment have unique properties for cleavage control that may have implications for gamma-secretase regulation and intracellular distribution.
Co-overexpression of presenilin-1 or APH-1 abrogated gamma-secretase inhibition probably through prevention of the incorporation of CRB2 into the gamma-secretase complex
This gene encodes a component of the gamma secretase complex that cleaves integral membrane proteins such as Notch receptors and beta-amyloid precursor protein. The gamma secretase complex contains this gene product, or the paralogous anterior pharynx defective 1 homolog B (APH1B), along with the presenilin, nicastrin, and presenilin enhancer-2 proteins. The precise function of this seven-transmembrane-domain protein is unknown though it is suspected of facilitating the association of nicastrin and presenilin in the gamma secretase complex as well as interacting with substrates of the gamma secretase complex prior to their proteolytic processing. Polymorphisms in a promoter region of this gene have been associated with an increased risk for developing sporadic Alzheimer's disease. Alternative splicing results in multiple protein-coding and non-protein-coding transcript variants.
gamma-secretase subunit APH-1A
, anterior pharynx defective 1 homolog A
, anterior pharynx defective 1 homolog A (C. elegans)
, N-acylaminoacyl-peptide hydrolase
, acylamino-acid-releasing enzyme-like
, presenilin-stabilization factor
, anterior pharynx defective 1a homolog