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)

Neurofibrillary changes throughout the brain were investigated for three relatives who carried the Swedish APP(670, 671) mutation which causes overproduction of Abeta40 and Abeta42. They differed in terms of APOE genotype, age at the onset of dementia, and disease duration (P1: epsilon2/3, age 57, 11 years; P2: epsilon2/3, age 61, 5 years; P3: epsilon4/4, age 44, 12 years). For each subject, paraffin-embedded sections from diverse anatomically and cytoarchitectonically well-preserved regions were stained using the modified Bielschowsky method. Neurofibrillary tangles (NFT) and neuritic plaques (NP) were counted, and the area occupied by plaque estimated (%NP). In addition, sections from the medial frontal gyrus were stained with monoclonal antibodies to APOE. The regional patterns of neurofibrillary changes were consistent with those for late-onset AD. Longer disease duration was associated with further accumulations in earlier-affected areas, with superficial cortical layers consistently containing higher %NP than deep layers. APOE epsilon4/4 was associated with deeper limbic and frontal NFT, with an excess of NP (especially in the outer parietal cortex) which stained heavily for APOE - as well as with very early onset. APP(670, 671) mutation carriers demonstrate regional brain neurofibrillary changes characteristic of late-onset Alzheimer's disease with evidence for more Abeta deposition for epsilon4/4 than epsilon2/3. This raises the possibility that early Braak Stage I-II lesions might also follow this pattern of promotion.
J Cell Mol Med
PMID:APOE polymorphism and clinical duration determine regional neuropathology in Swedish APP(670, 671) mutation carriers: implications for late-onset Alzheimer's disease. 1216 5

Alzheimer disease (AD) is a neurodegenerative disease affecting a large percentage of the elderly population. Preventative therapies for AD have been limited; however, epidemiological studies have demonstrated that estrogen replacement therapy may prevent or delay the onset of AD. Therefore, we utilized female mutant amyloid precursor protein transgenic mice (APP(SWE)), as a mouse model of AD-like pathology, to study the long-term effects of estrogen withdrawal. Interestingly, by 8 months of age 58% of the ovariectomized APP(SWE) mice had died, whereas there was no mortality in the sham ovariectomized APP(SWE) mice. This mortality was correlated with estrogen loss only in the APP(SEW) mice since background strain matched ovariectomized wild-type mice had virtually no mortality. Cerebral A beta levels in the surviving APP(SWE) ovariectomized females were increased by 50% compared to the sham ovariectomized APP(SWE) females. However, the levels of A beta in the ovariectomized APP(SWE) mice were still well below those observed in 2-year-old APP(SWE) mice that had A beta plaques. Therefore, the mildly increased A beta levels were not the suspected cause of death in these ovariectomized mice. Previous studies have demonstrated increased mortality in mice overexpressing mutant or wildtype APP independent of A beta accumulation; thus, estrogen withdrawal may potentiate this phenotype associated with APP overexpression.
J Mol Neurosci
PMID:Ovariectomy of young mutant amyloid precursor protein transgenic mice leads to increased mortality. 1221 74

The clearance and degradation of extracellular A beta is critical for regulating beta-amyloid deposition, a major hallmark of brains of patients with A beta in Alzheimer's Disease. The low-density lipoprotein receptor-related protein, LRP1, is a large endocytic receptor that significantly contributes to the balance between degradation and production of A beta. An extracellular portion of the LRP, known as the cluster II region can bind to the secreted form of APP (sAPP-KPI). We show here that a GST fusion protein containing the cluster II region of LRP can be used as a 'mini-receptor' that specifically binds to sAPP-KPI from conditioned cultured medium. The binding between the GST-LRP-cluster II fusion protein and sAPP-KPI can be inhibited with the strong binding ligand of LRP1, called receptor-associated protein (RAP). Furthermore, a cell-based in vitro assay system has been developed to monitor the production of total A beta and A beta(1-42) in the presence and absence of RAP in Chinese hamster ovary (CHO) cell lines both deficient in LRP and expressing LRP. A 3-day treatment of the L2 (CHO cells deficient in LRP and overexpressing APP751) and L3 (CHO cells expressing LRP and overexpressing APP751) cell lines with RAP showed a decrease in total A beta and, interestingly, also a decrease in the ratio of A beta42/A beta(total). This cell-based model system and LRP-cluster II mini-receptor will be very useful for screening novel compounds that can reduce A beta accumulation by inhibiting binding of APP-KPI to LRP1.
J Mol Neurosci
PMID:The role of the low-density lipoprotein receptor-related protein (LRP1) in Alzheimer's A beta generation: development of a cell-based model system. 1221 91

The Alzheimer's amyloid beta protein (A beta) precursor (APP) is proteolytically cleaved by beta-secretase to N- and C-terminal fragments sAPPbeta and CTFbeta, respectively. Subsequently, CTFbeta is cleaved by gamma-secretase to generate A beta. We previously showed that the levels of secreted A beta and sAPPbeta were significantly reduced upon removal of glycosylphosphatidylinositol (GPI)-anchored proteins from either primary brain cells or Chinese hamster ovary cultures. The results indicated that GPI-anchored proteins facilitated beta-secretase activity. In this report, we strengthen the previous findings by demonstrating that CTFbeta, like sAPPbeta, is also reduced upon removal of GPI-anchored proteins and that sAPPbeta does not accumulate in an intracellular compartment. This facilitation pathway does not appear to be important for the processing of a disease-linked mutant form of APP (670NL), known to be a superior beta-secretase substrate. A novel aspartyl protease, BACE, responsible for beta-secretase activity in the brain is not GPI-anchored. However, BACE in brain membranes accumulate in lipid rafts, a compartment marked by the accumulation of GPI-anchored proteins. This finding is consistent with the hypothesis that BACE interacts with GPI-anchored proteins that facilitate its activity possibly by chaperoning it into lipid rafts.
J Mol Neurosci
PMID:Lipid rafts play an important role in A beta biogenesis by regulating the beta-secretase pathway. 1221 90

The metalloprotease ADAM 10 is an important APP alpha-secretase candidate, but in vivo proof of this is lacking. Furthermore, invertebrate models point towards a key role of the ADAM 10 orthologues Kuzbanian and sup-17 in Notch signalling. In the mouse, this function is, however, currently attributed to ADAM 17/TACE, while the role of ADAM 10 remains unknown. We have created ADAM 10-deficient mice. They die at day 9.5 of embryogenesis with multiple defects of the developing central nervous system, somites, and cardiovascular system. In situ hybridization revealed a reduced expression of the Notch target gene hes-5 in the neural tube and an increased expression of the Notch ligand dll-1, supporting an important role for ADAM 10 in Notch signalling in the vertebrates as well. Since the early lethality precluded the establishment of primary neuronal cultures, APPs alpha generation was analyzed in embryonic fibroblasts and found to be preserved in 15 out of 17 independently generated ADAM 10-deficient fibroblast cell lines, albeit at a quantitatively more variable level than in controls, whereas a severe reduction was found in only two cases. The variability was not due to differences in genetic background or to variable expression of the alternative alpha-secretase candidates ADAM 9 and ADAM 17. These results indicate, therefore, either a regulation between ADAMs on the post-translational level or that other, not yet known, proteases are able to compensate for ADAM 10 deficiency. Thus, the observed variability, together with recent reports on tissue-specific expression patterns of ADAMs 9, 10 and 17, points to the existence of tissue-specific 'teams' of different proteases exerting alpha-secretase activity.
Hum Mol Genet 2002 Oct 01
PMID:The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. 1235 87

Missense mutations in presenilin 1 (PS1) gene are the most common cause of early onset familial Alzheimer's disease (FAD). AD pathogenic PS1 mutations result in elevated gamma-secretase cleavage of APP and diminished S3-site cleavage of Notch. We have previously described a PS1-hypomorphic mouse line that could survive postnatally with markedly reduced gamma-secretase cleavage of APP and S3-site cleavage of Notch, resulting in a Notch developmental phenotype similar to PS1-null mice. This model was exploited to identify genes whose expression is altered due to the loss of PS1. A global gene expression study by differential display was performed on whole brains of PS1-hypomorphic mice and their wild type siblings. In total, more than 16,000 bands corresponding to cDNAs were compared between the mutant and wild-type brains. This analysis identified 19 cDNAs showing significantly altered expression resulting from PS1 deficiency. Four of the identified cDNAs corresponded to genes that could be associated with AD or presenilin function. Hypoxia inducible factor 1a (Hif1a), NPRAP (delta-catenin) and cell division cycle 10 (CDC10) showed significantly reduced expression in the PS1-hypomorphic compared to wild-type brains, whereas expression of nucleoside diphosphate kinase sub-unit A (NDPK-A) was markedly elevated in the respective brains. Clarification of the possible role of these genes in AD and the basis for their differential expression induced by PS1-deficiency may provide insight into the disease, presenilin function and consequences of its loss, as well as possible deleterious effects of AD therapeutics aimed at inhibiting PS1.
Brain Res Mol Brain Res 2002 Dec 30
PMID:Differential display analysis of presenilin 1-deficient mouse brains. 1253 15

Gene delivery vectors need to fulfill several efficacy and safety criteria before they can be used in humans. Successful clinical application requires effective transgene expression with a minimum of vector-associated toxicity. We describe the use of posttranscriptional regulatory elements in plasmid and lentiviral vectors coding for luciferase. These constructs allow high-level gene expression in both neuronal and glial cells. Of the several elements that we tested, WPRE gave the highest level of expression. Further enhancements were obtained when WPRE was combined with sequences corresponding to the 3' or 5' untranslated regions (UTR) of eukaryotic mRNAs (tau 3'UTR, TH 3'UTR, and APP 5'UTR). In neuronal cells, WPRE and both tau 3'UTR and APP 5'UTR had an additive effect on expression. The combination of the three elements increased the basal level of expression by up to 26-fold. In glial cells, WPRE and APP 5'UTR had additive effects on expression, and their combination increased expression up to 10-fold. These results provide important information regarding the development of optimal CNS gene transfer vectors not only for gene therapy but also for the study of gene function.
Mol Ther 2003 Jun
PMID:Optimization of transgene expression at the posttranscriptional level in neural cells: implications for gene therapy. 1278 52

Alois Alzheimer described the concurrence of two conspicuous proteinacious aggregates in 1906. Today it is clear that the two types of protein aggregates are fundamentally different. One consists of a short fragment (Abeta peptide) of a membrane protein APP and is found mainly outside of cells and the other is formed from a biochemically modified cytoskeleton-associated protein known as tau. The latter is found exclusively inside cells. Aggregated tau in all tauopathies including AD is abnormally modified by the excess incorporation of chemical groups called phosphates (hyperphosphorylation), and the appearance of this biochemical change coincides with the onset all tauopathies, suggesting that it is both a necessary and sufficient cause for such diseases. Data indicate that the basis for tau hyperphosphorylation is the dysregulation of key enzymes known as kinases. These enzymes are therapeutic targets for AD and other neurodegenerative diseases, which feature pathological tau structures in brain
J Mol Neurosci 2003 Apr
PMID:Prospect of therapeutic approaches to tauopathies. 1279 13

Based on genetic findings, the relationship between the APP/Abeta and tau/tangle pathologies are discussed. It is argued that APP/Abeta is upstream of tau/tangle in the Alzheimer pathogenesis, and that the relationship between the pathologies are promiscuous in two ways: first, APP/Abeta can equally be seen to be upstream of synuclein/Lewy bodies in cell death pathways, and second, tau pathology can be initiated by genetic lesions in other pathways.
J Mol Neurosci 2003 Apr
PMID:The relationship between amyloid and tau. 1279 14

Although APP mutations associated with inherited forms of Alzheimer's disease (AD) are relatively rare, detailed studies of these mutations may prove critical for gaining important insights into the mechanism(s) and etiology of AD. Here, we present a detailed biophysical characterization of the structural properties of protofibrils formed by the Arctic variant (E22G) of amyloid-beta protein (Abeta40(ARC)) as well as the effect of Abeta40(WT) on the distribution of the protofibrillar species formed by Abeta40(ARC) by characterizing biologically relevant mixtures of both proteins that may mimic the situation in the heterozygous patients. These studies revealed that the Arctic mutation accelerates both Abeta oligomerization and fibrillogenesis in vitro. In addition, Abeta40(ARC) was observed to affect both the morphology and the size distribution of Abeta protofibrils. Electron microscopy examination of the protofibrils formed by Abeta40(ARC) revealed several morphologies, including: (1) relatively compact spherical particles roughly 4-5 nm in diameter; (2) annular pore-like protofibrils; (3) large spherical particles 18-25 nm in diameter; and (4) short filaments with chain-like morphology. Conversion of Abeta40(ARC) protofibrils to fibrils occurred more rapidly than protofibrils formed in mixed solutions of Abeta40(WT)/Abeta40(ARC), suggesting that co-incubation of Abeta40(ARC) with Abeta40(WT) leads to kinetic stabilization of Abeta40(ARC) protofibrils. An increase in the ratio of Abeta(WT)/Abeta(MUT(Arctic)), therefore, may result in the accumulation of potential neurotoxic protofibrils and acceleration of disease progression in familial Alzheimer's disease mutation carriers.
J Mol Biol 2003 Sep 26
PMID:Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores. 1297 52


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