Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-amyloid (Abeta) peptides are derived from the endoproteolytic processing of amyloid precursor protein (APP) and play a key role in the pathogenesis of Alzheimer's disease (AD). Beta-site APP-cleaving enzyme 1 ([BACE1] also known as beta-secretase) is responsible for cleaving APP to generate neurotoxic Abeta peptides in patients with AD. The BACE1 gene is located on chromosome 11q23.3, near the recently identified region with increased lod scores for AD. The biological functional and genetic association studies indicated that the BACE1 gene might be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To investigate an association between the BACE1 C786G polymorphism and sporadic LOAD in Chinese, we examined 105 LOAD patients and 130 healthy controls. Our results showed higher frequency of the 786G-allele in LOAD patients (38.6%) than that in controls (28.5%), and a statistical significance was observed for an association of the G-allele with LOAD (odds ratio [OR] = 1.58, 95% confidence interval [CI] 1.07-2.23, p = 0.02). We also found a synergetic interaction between the G-allele and apolipoprotein E allele 4 (APOE e4) status on the risk of LOAD (OR = 1.91, 95% CI 1.23-2.95, p = 0.003). These results suggest that BACE1 gene polymorphism C786G might act as an APOE epsilon4 allele-dependent risk factor for developing LOAD in Chinese.
J Mol Neurosci 2005
PMID:Genetic association of BACE1 gene polymorphism C786G with late-onset Alzheimer's disease in Chinese. 1578 60

Golgi-localized, gamma ear-containing, ADP ribosylation factor-binding (GGA) proteins have been shown to be implicated in the sorting of cargo proteins from the trans-Golgi network (TGN) to endosomal compartments. GGAs directly bind to DXXLL motifs in the cytoplasmic domains of cargo proteins. The Alzheimer-associated beta-secretase BACE1 also interacts with GGA proteins, but the functional relevance of this interaction was unknown. Here, we show that GGA1 regulates the retrograde transport of internalized BACE1 from endosomal compartments to the TGN by direct interaction in a phosphorylation-dependent manner. While phosphorylated BACE1 is efficiently transported from endosomes to the TGN, non-phosphorylated BACE1 enters a direct recycling route to the cell surface. Our data indicate that GGA proteins are not only involved in the sorting at the TGN but also mediate the retrograde transport of cargo proteins from endosomes to the TGN.
Mol Cell Neurosci 2005 Jul
PMID:GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network. 1588 16

Early diagnosis of Alzheimer's disease is important in initiating symptomatic treatment with acetylcholine esterase inhibitors, and will be of even greater significance if drugs with a potential to slow down the degenerative process, such as beta-secretase inhibitors and beta-amyloid vaccination, prove to have a clinical effect. During the last decade, research efforts have focused on developing cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease. In this review, the background and principles for, and the diagnostic performance of, the CSF biomarkers total tau, phosphorylated tau and the 42-amino acid form of beta-amyloid, are reviewed. New candidate CSF biomarkers and new strategies, including multiparameter immunoassays and CSF proteomics techniques, in the search of additional CSF biomarkers are also reviewed. Finally, the rationale for the use of CSF biomarkers to identify and monitor the biochemical effect of new drug candidates is reviewed.
Expert Rev Mol Diagn 2005 Sep
PMID:CSF biomarkers for Alzheimer's disease: use in early diagnosis and evaluation of drug treatment. 1614 70

The accumulation of the amyloid-beta peptide, the main constituent of the "amyloid plaque", is widely considered to be the key pathological event in Alzheimer's disease. Amyloid-beta is produced from the amyloid precursor protein through the action of the proteases beta-secretase and gamma-secretase. Alternative cleavage of amyloid precursor protein by the enzyme alpha-secretase precludes amyloid-beta production. In addition, several proteases are involved in the degradation of amyloid-beta. This review focuses on the proteolytic mechanisms of amyloid-beta metabolism. An increasingly detailed understanding of proteolysis in both amyloid-beta deposition and clearance has identified some of these proteases as potential therapeutic targets for Alzheimer's disease. A more complex knowledge of these proteases takes us one step closer to developing "disease-modifying" therapies, but these advances also emphasize that significant challenges must be overcome before clinically effective drugs to treat Alzheimer's disease become a reality.
Trends Mol Med 2005 Oct
PMID:Proteolytic mechanisms in amyloid-beta metabolism: therapeutic implications for Alzheimer's disease. 1615 92

A recent study showed that F-spondin, a protein associated with the extracellular matrix, interacted with amyloid precursor protein (APP) and inhibited beta-secretase cleavage. F-spondin contains a thrombospondin domain that we hypothesized could interact with the family of receptors for apolipoprotein E (apoE). Through coimmunoprecipitation experiments, we demonstrated that F-spondin interacts with an apoE receptor (apoE receptor 2 [ApoEr2]) through the thrombospondin domain of F-spondin and the ligand binding domain of ApoEr2. Full-length F-spondin increased coimmunoprecipitation of ApoEr2 and APP in transfected cells and primary neurons and increased surface expression of APP and ApoEr2. Full-length F-spondin, but none of the individual F-spondin domains, increased cleavage of APP and ApoEr2, resulting in more secreted forms of APP and ApoEr2 and more C-terminal fragments (CTF) of these proteins. In addition, full-length F-spondin, but not the individual domains, decreased production of the beta-CTF of APP and Abeta in transfected cells and primary neurons. The reduction in APP beta-CTF was blocked by receptor-associated protein (RAP), an inhibitor of lipoprotein receptors, implicating ApoEr2 in the altered proteolysis of APP. ApoEr2 coprecipitated with APP alpha- and beta-CTF, and F-spondin reduced the levels of APP intracellular domain signaling, suggesting that there are also intracellular interactions between APP and ApoEr2, perhaps involving adaptor proteins. These studies suggest that the extracellular matrix molecule F-spondin can cluster APP and ApoEr2 together on the cell surface and affect the processing of each, resulting in decreased production of Abeta.
Mol Cell Biol 2005 Nov
PMID:F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein. 1622 78

Computing the binding affinity of a protein-ligand complex is one of the most fundamental and difficult tasks in computer-aided drug design. Many approaches for computing binding affinities can be classified as linear interaction energy (LIE) models as they rely on some type of linear fit of computed interaction energies between ligand and protein. We have examined the computed interaction energies of a series of beta-secretase (BACE) inhibitors in terms of van der Waals, coulombic, and continuum-solvation contributions to ligand binding. We have also systematically examined the effect of different protonation states of the protein and ligands. We find that the binding affinities are relatively insensitive to the protonation state of the protein when neutral ligands are considered. Inclusion of charged ligands leads to large deviations in the coulomb, solvation, and even van der Waals terms. The latter is due to increased repulsive van der Waals interactions in the complex due to the strong coulomb attraction found between oppositely charged functional groups in the protein and ligand. In general, we find that the best models are obtained when the protein is judiciously charged (e.g. Asp32-, Arg235+) and the potentially charged ligands are treated as neutral.
J Mol Graph Model 2006 May
PMID:Linear interaction energy models for beta-secretase (BACE) inhibitors: Role of van der Waals, electrostatic, and continuum-solvation terms. 1629 30

Reticulons (RTNs) are a group of integral membrane proteins that have a uniquely conserved C-terminal domain named RHD. In mammalian genomes, transcripts are produced from four genes, rtn1 to rtn4, under the regulation of tissue or cell-type-specific expression. The presence of alternative promoters for gene expression and multiple cryptic splicing sites have resulted in large numbers of genes/proteins that are classified among the reticulon family. Although this family exists in almost all eukaryotes, only the rtn4 gene product, Nogo (RTN4), has gained relatively more in-depth attention. Despite predominant localization in the endoplasmic reticulum, Nogo on the cell surface appears to play a critical role as an inhibitory molecule for axonal growth and regeneration in humans and rodents. Recently, studies have expanded the biological functions of RTNs to other facets including modulating the enzymatic activity of beta-secretase in Alzheimer's disease. In this review, we summarize the accumulated findings concerning the structural and functional aspects of RTNs and speculate on their linkage to the pathogenesis of neurodegenerative diseases.
Cell Mol Life Sci 2006 Apr
PMID:Reticulon proteins: emerging players in neurodegenerative diseases. 1650 74

beta-Site beta-amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the beta-secretase in vivo for processing APP to generate amyloid beta protein (Abeta). Abeta deposition in the brain is the hallmark of Alzheimer's disease (AD) neuropathology. Inhibition of BACE1 activity has major pharmaceutical potential for AD treatment. The expression of the BACE1 gene is relatively low in vivo. The control of BACE1 expression has not been well defined. There are six upstream AUGs (uAUGs) in the 5' leader sequence of the human BACE1 mRNA. We investigated the role of the promoter and the uATGs in the 5' untranslated region (UTR) of the human BACE1 gene in BACE1 gene transcription and translation initiation. Our results show that the first and second uATGs are the integral part of the core minimal promoter of the human BACE1 gene, while the third uAUG is skipped over by ribosomal scanning. The fourth uAUG can function as a translation initiation codon, and deletion or mutation of this uAUG increases downstream gene expression. The fourth uAUG of the BACE1 5'UTR is responsible for inhibiting the expression of BACE1. Translation initiation by the BACE1 uAUGs and physiological AUG requires intact eIF4G. Our results demonstrate that during human BACE1 gene expression, ribosomes skipped some uAUGs by leaky scanning and translated an upstream open reading frame, initiated efficiently at the fourth uAUG, and subsequently reinitiated BACE1 translation at the physiological AUG site. Such leaky scanning and reinitiation resulted in weak expression of BACE1 under normal conditions. Alterations of the leaky scanning and reinitiation in BACE1 gene expression could play an important role in AD pathogenesis.
Mol Cell Biol 2006 May
PMID:Leaky scanning and reinitiation regulate BACE1 gene expression. 1661 80

Lipid rafts provide a platform for regulating cellular functions and participate in the pathogenesis of several diseases. However, the role of caveolin-1 in this process has not been elucidated definitely in neuron. Thus, this study was performed to examine whether caveolin-1 can regulate amyloid precursor protein (APP) processing in neuronal cells and to identify the molecular mechanisms involved in this regulation. Caveolin-1 is up-regulated in all parts of old rat brain, namely hippocampus, cerebral cortex and in elderly human cerebral cortex. Moreover, detergent-insoluble glycolipid (DIG) fractions indicated that caveolin-1 was co-localized with APP in caveolae-like structures. In DIG fractions, beta APP secretion was up-regulated by caveolin-1 over- expression, which was modulated via protein kinase C (PKC) in neuroblastoma cells. From these results we conclude that caveolin-1 is selectively expressed in senescent neurons and that it induces the processing of APP by beta-secretase via PKC downregulation.
Exp Mol Med 2006 Apr 30
PMID:Caveolin-1 upregulation in senescent neurons alters amyloid precursor protein processing. 1667 66

The amyloid-beta (Abeta) peptide, the proteolytic fragment of Abeta precursor protein (APP), aggregates and forms neuritic plaques, a major hallmark of Alzheimer's disease (AD). The limiting step in generating the Abeta peptide from APP is cleavage by the beta-secretase enzyme, BACE1. Regulation of the BACE1 gene is likely to play an important role in AD etiology and treatment. We therefore studied the activity of a 4.1-kb 5'-flanking region (-3765/+364, +1 being the transcription start site) of the BACE1 gene, both in 5'- and 3'-deletion series and through Northern blotting. We show that the BACE1 promoter has regulatory activity throughout the 4.1-kb length, both positive and negative, and that this activity can be quantitatively modeled according to promoter sequence length, with the specific model depending on the presence of negative regulatory elements as the 5'- most portion of the sequence. We also examined a previously identified 141-bp proximal fragment (+224/+364) of the BACE1 promoter and two constituent (91- and 50-bp) subfragments. We report that the 91-bp fragment (+224/+314) is the most likely seat of neuronal expression of the BACE1 gene and that it is the portion of the 141-bp fragment that accounts for observed DNA-protein interactions in brain extracts. The 50-bp fragment (+315/+364), which showed significant reporter gene activity from the empty vector, binds nuclear proteins in a cell type-specific manner and contains the AP2 site as shown by the electrophoretic mobility shift assay. Overall, the 141-bp fragment had no strong matches within GenBank, and the 91-bp fragment is predicted to have several potential stem-loop sites. Taken together, BACE1 gene promoter activity is differentially regulated, and the 91-bp fragment represents a novel promoter region for cell type-specific regulation. This fragment might be a useful target to regulate BACE1 expression leading to Abeta production and to understand the neuropathogenesis of AD.
J Mol Neurosci 2006
PMID:BACE1 gene promoter is differentially regulated: detection of a novel promoter region for its cell type-specific regulation. 1667 58


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