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)

The APOE epsilon4 allele is the most significant genetic risk factor associated with Alzheimer's disease to date. Epidemiological studies have demonstrated that inheritance of one or more epsilon4 alleles affects both the age of onset and the severity of pathology development. Dosage of APOE epsilon2 and epsilon3 alleles, however, appear to be protective against the effects of epsilon4. Although much of the biology of APOE in peripheral cholesterol metabolism is understood, its role in brain cholesterol metabolism and its impact on AD development is less defined. Several APOE transgenic models have been generated to study the effects of APOE alleles on APP processing and Abeta pathology. However, these models have potential limitations that confound our understanding of the effects of apolipoprotein E (APOE) levels and cholesterol metabolism on disease development. To circumvent these limitations, we have taken a genomic-based approach to better understand the relationship between APOE alleles, cholesterol and Abeta metabolism. We have characterized APOE knock-in mice, which express each human allele under the endogenous regulatory elements, on a defined C57BL6/J background. These mice have significantly different serum cholesterol levels and steady-state brain APOE levels, and yet have equivalent brain cholesterol levels. However, the presence of human APOE significantly increases brain Abeta levels in a genomic-based model of AD, irrespective of genotype. These data indicate an independent role for APOE in cholesterol metabolism in the periphery relative to the CNS, and that the altered levels of cholesterol and APOE in these mice are insufficient to influence Abeta metabolism in a mouse model of Alzheimer's disease.
Hum Mol Genet 2004 Sep 01
PMID:Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model. 1522 91

The 140-amino-acid protein alpha-synuclein (alpha-syn) is the major constituent of Lewy bodies. The protein interacts with several intracellular signal transduction pathways. Reasons for onset of abnormal aggregation of alpha-syn are unclear. Metal ions, oxidative stress, and beta-amyloid 1-42 (Abeta1-42) are important induction factors for alpha-syn aggregation. beta-Synuclein (beta-syn) can counteract alpha-syn aggregation. Cross-breeding of beta-syn transgenic mice with animals overexpressing alpha-syn significantly decreased alpha-syn-positive neuronal inclusion bodies and improved motor function. This was an important proof of concept for the role of beta-syn in regulating alpha-syn aggregation. A drug discovery program based on peptide derivatives (N-terminal amino acids 1-15) of beta-syn was initiated. For screening, tissue culture models simulating disease-specific conditions were utilized. They protected against growth factor withdrawal, Abeta toxicity, and oxidative stress. Three peptides were selected (KEGV, SMAKEGV, MDFMKGLSMAKE) for in vivo studies because they also decreased expression of Abeta1-40 and Abeta1-42. First, in vivo experiments were made in human amyloid precursor protein (APP [Swedish and London mutation]) transgenic mice, as well as alpha-syn transgenic mice. Treatment was performed with the peptides as an intraperitoneal injection or as intranasal droplets for 2 mo. Behavioral studies in APP transgenic mice were performed after 1 and 2 mo of treatment and showed clear effects of these peptides.
J Mol Neurosci 2004
PMID:Beta-Synuclein-derived peptides with neuroprotective activity: an alternative treatment of neurodegenerative disorders? 1531 65

The response of the hippocampal proteome to expression of mutant proteins present in familial forms of Alzheimer's disease (AD) was studied using transgenic rats. These animals carry both the amyloid precursor protein Swedish and 717 mutation (APP(SW+717)) as well as the presenilin 1 Finnish mutation (PS1(FINN)). This transgenic rat model displays intracellular amyloid beta (Abeta) in neurons of the neocortex and the hippocampus (CA2 and CA3). The hippocampus was selected as it is one of the first brain regions affected in AD and is involved in the processing of short-term memory and spatial memory. Applying a proteomic approach, we demonstrate that the expression of APP(SW+717) and PS1(FINN) transgenes causes changes in expression of hippocampal proteins, some of which have been previously linked to learning and memory formation. The protein alterations documented here occur in the absence of plaque formation and prior to the onset of cognitive deficits later observed in these transgenic rats. This indicates that molecular changes take place in the hippocampal neurons in response to expression of mutant proteins APP(SW+717) and PS1(FINN), which precede the occurrence of overt extracellular accumulation of extracellular amyloid. The implications of these findings on our understanding of the early stages of AD are discussed.
Brain Res Mol Brain Res 2004 Dec 20
PMID:Early dysregulation of hippocampal proteins in transgenic rats with Alzheimer's disease-linked mutations in amyloid precursor protein and presenilin 1. 1558 62

Abnormal tau phosphorylation occurs in several neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here, we compare mechanisms of tau phosphorylation in mouse models of FTDP-17 and AD. Mice expressing a mutated form of human tau associated with FTDP-17 (tau(V337M)) showed age-related increases in exogenous tau phosphorylation in the absence of increased activation status of a number of kinases known to phosphorylate tau in vitro. In a "combined" model, expressing both tau(V337M) and the familial amyloid precursor protein AD mutation APP(V717I) in a CT100 fragment, age-dependent tau phosphorylation occurred at the same sites and was significantly augmented compared to "single" tau(V337M) mice. These effects were concomitant with increased activation status of mitogen-activated protein kinase (MAPK) family members (extracellular regulated kinases 1 and 2, p38, and c-Jun NH(2)-terminal kinase) but not glycogen synthase kinase-3alphabeta or cyclin-dependent kinase 5. The increase in MAPK activation was a discrete effect of APP(V717I)-CT100 transgene expression as near identical changes were observed in single APP(V717I)-CT100 mice. Age-dependent deficits in memory were also associated with tau(V337M) and APP(V717I)-CT100 expression. The data reveal distinct routes to abnormal tau phosphorylation in models of AD and FTDP-17 and suggest that in AD, tau irregularities may be linked to processing of APP C-terminal fragments via specific effects on MAPK activation status.
Mol Cell Biol 2005 Jan
PMID:Increased tau phosphorylation on mitogen-activated protein kinase consensus sites and cognitive decline in transgenic models for Alzheimer's disease and FTDP-17: evidence for distinct molecular processes underlying tau abnormalities. 1560 49

Copper is an essential metal in living organisms; thus, the maintenance of adequate copper levels is of vital importance and is highly regulated. Dysfunction of copper metabolism leading to its excess or deficiency results in severe ailments. Two examples of illnesses related to alterations in copper metabolism are Menkes and Wilson diseases. Several proteins are involved in the maintenance of copper homeostasis, including copper transporters and metal chaperones. In the last several years, the beta-amyloid-precursor protein (beta-APP) and the prion protein (PrP(C)), which are related to the neurodegenerative disorders Alzheimer and prion diseases respectively, have been associated with copper metabolism. Both proteins bind copper through copper-binding domains that also have been shown to reduce copper in vitro. Moreover, this ability to reduce copper is associated with a neuroprotective effect exerted by the copper-binding domain of both proteins against copper in vivo. In addition to a functional link between copper and beta-APP or PrP(C), evidence suggests that copper has a role in Alzheimer and prion diseases. Here, we review the evidence that supports both, the role of beta-APP and PrP(C), in copper metabolism and the putative role of copper in neurodegenerative diseases.
Mol Aspects Med
PMID:Is there a role for copper in neurodegenerative diseases? 1611 88

The amyloid-beta precursor-like protein APLP2 is structurally and functionally related to the amyloid-beta precursor protein APP, the protein generally accepted to be involved in Alzheimer's disease. Since we previously observed that the levels of APP mRNA and protein were up-regulated threefold in the active intermediate pituitary melanotrope cells of black-adapted Xenopus laevis, we now decided to study the regulation of APLP2 in these physiologically inducible neuroendocrine cells. Interestingly, both the mRNA and protein levels of Xenopus APLP2 were similar in the melanotrope cells of black and white frogs. Newly synthesized APLP2 became glycosylated and sulfated, chondroitin sulfate glycosaminoglycan chains were added, and eventually the protein was proteolytically cleaved. Unlike for APP, no phosphorylated APLP2 was observed. Our results show that, although APP and APLP2 are thought to be functionally related, their responses to neuroendocrine cell activation differ, suggesting distinct roles for these proteins.
Mol Cell Neurosci 2005 Nov
PMID:The amyloid-beta precursor-like protein APLP2 and its relative APP are differentially regulated during neuroendocrine cell activation. 1615 62

Key pathological processes in Alzheimer's disease (AD) include the accumulation of amyloid beta peptide (Abeta) which, in excess, triggers pathological cascades including widespread inflammation, partly reflected by chronic microglial activation. It has previously been suggested that CD40/CD40L interaction promotes AD like pathology in transgenic mice. Thus, amyloid burden, gliosis and hyperphosphorylation of tau are all reduced in transgenic models of AD lacking functional CD40L. We therefore hypothesized that cellular events leading to altered APP metabolism, inflammation and increased tau phosphorylation underlying these observations would be regulated at the genomic level. In the present report, we used the Affymetrix (GeneChip) oligonucleotide microarray U133A to gain insight into the global and simultaneous transcriptomic changes in response to microglia activation after CD40/CD40L ligation. As expected, regulation of elements of the NF-kappaB signaling, chemokine and B cell signaling pathways was observed. Taken together, our data also suggest that CD40 ligation in human microglia specifically perturbs many genes associated with APP processing.
Brain Res Mol Brain Res 2005 Oct 31
PMID:Genomic regulation after CD40 stimulation in microglia: relevance to Alzheimer's disease. 1618 6

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert anti-inflammatory, analgesic, and antipyretic activities and suppress prostaglandin synthesis by inhibiting cyclooxygenase, an enzyme that catalyzes the formation of prostaglandin precursors from arachidonic acid. Epidemiological observations indicate that the long-term treatment of patients suffering from rheumatoid arthritis with NSAIDs results in reduced risk and delayed onset of Alzheimer's disease. In this study, we investigated the therapeutic potential for Alzheimer's disease of mefenamic acid, a commonly used NSAID that is a cyclooxygenase-1 and 2 inhibitor with only moderate anti-inflammatory properties. We found that mefenamic acid attenuates the neurotoxicities induced by amyloid beta peptide (Abeta)(1-42) treatment and the expression of a Swedish double mutation (KM595/596NL) of amyloid precursor protein (Swe-APP) or the C-terminal fragments of APP (APP-CTs) in neuronal cells. We also show that mefenamic acid decreases the production of the free radical nitric oxide and reduces cytochrome c release from mitochondria induced by Abeta(1-42), Swe-APP, or APP-CTs in neuronal cells. In addition, mefenamic acid up-regulates expression of the antiapoptotic protein Bcl-X(L). Moreover, our study demonstrates for the first time that mefenamic acid improves learning and memory impairment in an Abeta(1-42)-infused Alzheimer's disease rat model. Taking these in vitro and in vivo results together, our study suggests that mefenamic acid could be used as a therapeutic agent in Alzheimer's disease.
Mol Pharmacol 2006 Jan
PMID:Mefenamic acid shows neuroprotective effects and improves cognitive impairment in in vitro and in vivo Alzheimer's disease models. 1622 58

APP, amyloid beta precursor protein, is linked to the onset of Alzheimer's disease (AD). We have here found that transforming growth factor beta2 (TGFbeta2), but not TGFbeta1, binds to APP. The binding affinity of TGFbeta2 to APP is lower than the binding affinity of TGFbeta2 to the TGFbeta receptor. On binding to APP, TGFbeta2 activates an APP-mediated death pathway via heterotrimeric G protein G(o), c-Jun N-terminal kinase, NADPH oxidase, and caspase 3 and/or related caspases. Overall degrees of TGFbeta2-induced death are larger in cells expressing a familial AD-related mutant APP than in those expressing wild-type APP. Consequently, superphysiological concentrations of TGFbeta2 induce neuronal death in primary cortical neurons, whose one allele of the APP gene is knocked in with the V642I mutation. Combined with the finding indicated by several earlier reports that both neural and glial expression of TGFbeta2 was upregulated in AD brains, it is speculated that TGFbeta2 may contribute to the development of AD-related neuronal cell death.
Mol Cell Biol 2005 Nov
PMID:Transforming growth factor beta2 is a neuronal death-inducing ligand for amyloid-beta precursor protein. 1622 82

Alzheimer's disease (AD) is an age-related disease, which affects approximately 40% of the population at an age above 90 years. The heritability is estimated to be greater than 60% and there are rare autosomal dominant forms indicating a significant genetic influence on the disease process. Despite the successes in the early 1990s when four genes were identified, which directly cause the disease (APP, PSEN1 and PSEN2) or greatly increase the risk of disease development (APOE), it has proved exceedingly difficult to identify additional genes involved in the pathogenesis. However, several linkage and association studies have repeatedly supported the presence of susceptibility genes on chromosomes (chrms) 9, 10 and 12. The study populations have, however, mostly been of great genetic heterogeneity, and this may have contributed to the meagre successes in identifying the disease associated genetic variants. In this study, we have performed a genome wide linkage study on 71 AD families from the relatively genetically homogeneous Swedish population where it is also possible to study the genetic ancestry in public databases. We have performed nonparametric linkage analyses in the total family material as well as stratified the families with respect to the presence or absence of APOE varepsilon4. Our results suggest that the families included in this study are tightly linked to the APOE region, but do not show evidence of linkage to the previously reported linkages on chrms 9, 10 and 12. Instead, we observed the next highest LOD score on chromosome 5q35 in the total material. Further, the data suggest that the major fraction of families linked to this region is APOE varepsilon4 positive.
Mol Psychiatry 2006 Feb
PMID:Genome scan on Swedish Alzheimer's disease families. 1628 13


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