Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The beta-amyloid peptides derived by proteolytic cleavage from the amyloid precursor protein (APP) play a major role in the pathogenesis of Alzheimer's disease (AD) by forming aggregated, fibrillary complexes that have been shown to be neurotoxic. The beta-site APP-cleaving enzyme (BACE1) has been identified as the key enzyme leading to beta-amyloid formation, and cholinergic mechanisms have been shown to control APP processing. The present study sought to determine whether BACE1 expression is controlled by muscarinic acetylcholine receptor (mAChR) subtypes in the neuroblastoma cell line SK-SH-SY5Y. Stimulation of cells with the M1/M3-selective mAChR agonist talsaclidine for 1 hr resulted in a dose-dependent increase in BACE1 expression up to twofold over basal levels. Similar effects of BACE1 up-regulation were observed when protein kinase C was directly activated by phorbol esters. However, when the MAP kinases MEK/ERK were inhibited, BACE1 expression was no longer up-regulated by the activation of M1-mAChR. In contrast, BACE1 expression was suppressed by stimulation of M2-mediated pathways via selective M2-agonist binding or direct activation of adenylate cyclase with forskolin, an effect that was prevented by inhibiting protein kinase A. These results may explain the observed deterioration of AD patients after initial improvements with AChE inhibitor or M1-mAChR agonist treatment.
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PMID:Beta-secretase BACE1 is differentially controlled through muscarinic acetylcholine receptor signaling. 1521 91

beta-Amyloid peptide accumulates in the brain of patients affected by sporadic or familial forms of Alzheimer's disease. It derives from the proteolytic attacks of the beta-amyloid precursor protein (betaAPP) by beta- and gamma-secretase activities. An additional epsilon cleavage taking place a few residues C-terminal to the gamma-site has been reported, leading to the formation of an intracellular fragment referred to as APP intracellular domain C50. This epsilon cleavage received particular attention because it resembles the S3 Notch cleavage generating Notch intracellular domain. Indeed, APP intracellular domain, like its Notch counterpart, appears to mediate important physiological functions. gamma and epsilon cleavages on betaAPP appear spatio-temporally linked but pharmacologically distinct and discriminable by mutagenesis approaches. As these cleavages could be seen as either deleterious (gamma-site) or beneficial (epsilon-site), it appears of most interest to set up models aimed at studying these activities separately, particularly to design specific and bioavailable inhibitors. On the other hand, it is important to respect the topology of the substrates in order to examine physiologically relevant cleavages. Here we describe the obtention of cells overexpressing APPepsilon, the epsilon-secretase-derived N-terminal fragment of betaAPP. Interestingly, this N-terminal fragment of betaAPP was shown by biochemical and immunohistochemical approaches to behave as a genuine membrane-bound protein. APPepsilon undergoes constitutive and protein kinase C-regulated alpha-secretase cleavages. Furthermore, APPepsilon is targeted by the beta-secretase beta-site APP-cleaving enzyme and is subsequently cleaved by gamma-secretase. The resulting beta-amyloid peptide production is fully prevented by various gamma-secretase inhibitors. Altogether, our study shows that APPepsilon is a relevant betaAPP derivative to study gamma-secretase activities and to design specific inhibitors without facing any rate-limiting effect of epsilon-secretase-derived cleavage.
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PMID:APPepsilon, the epsilon-secretase-derived N-terminal product of the beta-amyloid precursor protein, behaves as a type I protein and undergoes alpha-, beta-, and gamma-secretase cleavages. 1652 70