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)

Apolipoprotein-E-deficient mice provide a useful model system for studying the role of apolipoprotein E (apoE) in brain function. In the present study, we characterized the cholinergic function of these mice and the extent of phosphorylation of their cytoskeletal protein tau. Morris water maze tasks revealed deficits in working memory that were accompanied by a specific decrease in hippocampal and cortical choline acetyltransferase activities. Immunoblot experiments utilizing native and dephosphorylated tau and antibodies directed against specific phosphorylated and unphosphorylated tau epitopes revealed that tau of the apoE-deficient mice is hyperphosphorylated. These results show that apoE-deficient mice have cognitive cholinergic and cytoskeletal derangements and point out the importance of this model for studying the role of apoE in neuronal function.
Mol Chem Neuropathol
PMID:Biochemical and cognitive studies of apolipoprotein-E-deficient mice. 887 47

Infectious agents have been proposed as possible etiological factors in sporadic cases of Alzheimer disease (AD), herpes simplex type 1 virus (HSV1) being a likely candidate. We have detected laten HSV1 in brain from AD patients and from aged normal individuals, using polymerase chain reaction (PCR), in the regions most affected in the disease. In contrast, we have not detected another neurotropic herpes virus, varicella zoster (VZV), in any brains. We have postulated that HSV1 reactivates periodically, and that a host or viral characteristic determines the degree of damage caused by the resulting acute infection-with much greater damage in the case of AD patients. We have therefore examined a host factor-the apolipoprotein E (apoE) genotype, since the E4 allele is a known risk factor in the disease. We have found that the risk of developing AD is much greater in those who are HSV1-positive in brain and who possess an apoE4 allele than for those with only one of these factors.
Mol Chem Neuropathol
PMID:Neurotropic viruses and Alzheimer disease. Interaction of herpes simplex type 1 virus and apolipoprotein E in the etiology of the disease. 887 52

Transient increases in triglycerides and cholesterol were found in rat liver immediately after birth. Plasma VLDL and HDL increased after birth and reached a plateau after one week of life. The content of cholesterol ester was low at birth in all lipoproteins and increased in LDL and HDL during the first week of life. After birth, VLDL became enriched in apolipoproteins C and E, whereas HDL was enriched in apolipoprotein C and depressed in apolipoprotein E. The developmental changes in plasma lipoprotein levels and compositions in rats during the first week of life are comparable to those described in humans.
Comp Biochem Physiol B Biochem Mol Biol 1996 Apr
PMID:Changes in plasma lipoproteins and liver lipids in neonatal rats. 892 46

Polymorphisms in the genes for the low-density lipoprotein (LDL) receptor ligands, apolipoprotein E (apoE), and apolipoprotein B (apoB) are associated with variation in plasma levels of LDL cholesterol. Lp(a) lipoprotein(a) [Lp(a)] is LDL in which apoB is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined isoforms differing in molecular weight, which are inversely correlated with Lp(a) concentrations in blood. The interaction of apo(a) with triglyceride-rich lipoproteins differs with the size of apo(a), and therefore the effects of apoE gene polymorphism on Lp(a) levels could also depend on apo(a) size. We have investigated the possible effect of genetic variation in the apoE and apoB genes on plasma Lp(a) concentrations in 466 white men with different apo(a) phenotypes. Overall there was no significant association between the common apoE polymorphism and Lp(a), but in the subgroup with apo(a)-S4, concentrations of Lp(a) differed significantly among the apoE genotypes (P = 0.05). Lp(a) was highest in the apoE genotypes epsilon 2 epsilon 3 and epsilon 3 epsilon 3 and lowest in genotype epsilon 3 epsilon 4, and the apoE polymorphism was estimated to account for about 2.4% of the variation in Lp(a). In contrast, in the subgroup with apo(a)-S2 Lp(a) was significantly lower (P = 0.04) in apoE genotype epsilon 2 epsilon 3 than in genotype epsilon 3 epsilon 3. Lp(a) concentrations did not differ among the XbaI (P = 0.65) or SP 24/27 (P = 0.26) polymorphisms of the apoB gene. The expected effects of both apoE and apoB polymorphism on LDL levels were significant in the whole population sample and in subjects with large-sized apo(a) isoforms (P < 0.01), whereas no effect was seen in those with low molecular weight apo(a) isoforms. We conclude that the influence of apoE genotypes on Lp(a) concentrations depends on the size of the apo(a) molecule in Lp(a), possibly because both apo(a)-S4 and apoE4 have high affinity for triglyceride-rich lipoproteins and may be taken up and degraded rapidly by remnant receptors.
J Mol Med (Berl) 1996 Nov
PMID:Effects of apoE gene polymorphism on Lp(a) concentrations depend on the size of apo(a): a study of 466 white men. 895 54

Amyloid precursor protein (APP) is metabolised to produce A beta, a peptide found aggregated in Alzheimer's disease neuritic plaques. APP is a member of a multigene protein family which includes amyloid precursor-like protein 2 (APLP2). Since A beta accumulation can be triggered by factors acting up- or downstream of APP processing, we investigated whether APP mRNA expression was altered in Alzheimer's disease post-mortem cerebral cortex. In addition, we characterised cortical APLP2 mRNA levels. Quantitative RNA-RNA solution hybridisation-RNase protection was used to assay total APP. APP containing the Kunitz-type protease inhibitor (KPI) insert and APLP2 mRNA in mid-temporal and superior frontal cortices from apolipoprotein E-genotyped subjects with Alzheimer's disease, other neurological diseases and non-demented controls. Approximately 3 times more APP than APLP2 mRNA was detected and about 70% of total APP mRNA contained the KPI insert in the control subjects. Total APP and APLP2 mRNA levels were significantly reduced in Alzheimer's disease mid-temporal, but not superior frontal cortex, suggesting that regional reductions in these mRNA correlate with severity of disease pathology. A small significant increase in the proportion of APP KPI mRNA was seen in both cortical regions in Alzheimer's disease. Apolipoprotein E genotype did not influence cortical levels of total APP, APP KPI or APLP2 mRNA. Alzheimer's disease-related increases in tissue DNA content were seen in both regions studied, while tissue RNA levels were reduced in the positive disease controls. In summary, these results indicate that Alzheimer's disease is not associated with over-expression of either APP or APLP2 mRNA. Our findings reveal a disease-associated increase in the proportion of APP KPI-containing isoforms, and further investigation should clarify whether this predisposes affected individuals to A beta production and aggregation, or reflects later events such as gliosis and neuronal cell death.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Quantification of APP and APLP2 mRNA in APOE genotyped Alzheimer's disease brains. 903 22

Lysosomal proteinases (cathepsins) and their endogenous inhibitors (cystatins) have been found to be closely associated with senile plaques, cerebrovascular amyloid deposits, and neurofibrillary tangles in Alzheimer disease (AD). Further, profound changes in the lysosomal system seem to be an early event in "at-risk" neurons of AD brains. There is an ongoing controversy as to whether lysosome-associated proteolytic mechanisms are causally related to the development and/or further progression of the disease. The present article deals with some arguments "pro" and "contra" an involvement of the endosomal/lysosomal pathway in amyloidogenesis as a cardinal process in AD. Other putative targets of acidic proteinases and their natural inhibitors in the pathogenesis of AD (such as formation of neurofibrillary tangles and regulation of apolipoprotein E) are also discussed.
Mol Chem Neuropathol 1996 Apr
PMID:The possible place of cathepsins and cystatins in the puzzle of Alzheimer disease: a review. 914 10

Progressive hypocholesterolemia is a feature associated with a number of cancers of different origin, and it is caused by the high expression of low-density lipoprotein (LDL) receptors (LDLrs) on many tumor cell types. Selective delivery of chemotherapeutics using LDL as a carrier has therefore been proposed, but the endogenous nature of LDL hampers its pharmaceutical application. In the current study, we explored the possibility of synthesizing liposomes that mimic LDL from commercially available lipids and proteins. Small unilamellar liposomes were created (28.9 +/- 0.9 nm) and complexed with 5.8 +/- 0.7 molecules of human recombinant apolipoprotein E (apoE). On intravenous injection into rats, the liposomes retained their aqueous core, structural integrity, and the majority of the preassociated apoE. [3H]Cholesteryl oleate-labeled apoE-enriched liposomes showed a relatively long serum half-life (>5 hr), and a low uptake by cells of the reticuloendothelial system was observed (<0.8% of the injected dose at 30 min after injection). Pretreatment of rats with 17alpha-ethinyl estradiol, which induces the expression of the LDLr on the liver and adrenals, led to a 2.5-fold accelerated serum clearance (t1/2 = 123 +/- 10 min) and a selectively increased uptake of liposomes by the liver (2.0-fold) and adrenals (3.8-fold). The liver association of the liposomes was coupled to the lysosomal uptake route, similarly as for LDL. In vitro studies using B16 melanoma cells showed that the liposomes bound exclusively to the LDLr via their apoE moiety (90,000 liposomes/cell), with a 14-fold higher affinity (Kd = 0.77 +/- 0.09 nM) than LDL itself. Because of their favorable properties, we anticipate that these apoE-enriched liposomes are advantageous compared with native LDL in the development of a selective LDLr-targeted antitumor therapy.
Mol Pharmacol 1997 Sep
PMID:Human recombinant apolipoprotein E-enriched liposomes can mimic low-density lipoproteins as carriers for the site-specific delivery of antitumor agents. 928 7

The allelic frequency of the gene for the K variant of butyrylcholinesterase (BCHE-K) was 0.17 in 74 subjects with late-onset (age > 65 years) histopathologically diagnosed Alzheimer's disease (AD), which was higher than the frequencies in 104 elderly control subjects (0.09), in 14 early-onset cases of confirmed AD (0.07) and in 29 confirmed cases of other dementia (0.10). The association of BCHE-K with late-onset AD was limited to carriers of the epsilon 4 allele of the apolipoprotein E gene (APOE), among whom the presence of BCHE-K gave an odds ratio of confirmed late-onset AD of 6.9 (95% C.I. 1.65-29) in subjects > 65 years and of 12.8 (1.9-86) in subjects > 75 years. In APOE epsilon 4 carriers over 75 years, only 1/22 controls, compared with 10/24 confirmed late-onset AD cases, had BCHE-K. We suggest that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon 4 as a susceptibility gene for late-onset AD.
Hum Mol Genet 1997 Oct
PMID:Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease. 930 73

We have shown that apolipoprotein E (ApoE) is synthesized by Muller cells, the major glial cell of the rabbit retina, and secreted into the vitreous after which it is taken up by retinal ganglion cells and rapidly transported into the optic nerve [Amaratunga et al., J. Biol. Chem. 271 (1996) 5628-5632]. In this report we demonstrate that the ApoE secreted by Muller cells in vivo and in culture is efficiently assembled into lipoprotein particles. Apolipoprotein J (ApoJ) is also synthesized by these cells and assembled into lipoprotein particles. The lipoproteins are triglyceride-rich and contain cholesterol esters and free cholesterol. They are heterogeneous, with densities between 1.006 and 1.18 and diameters between 14 and 45 nm. We discuss the possible role of these lipoproteins in supplying the needs of neurons for lipids, especially long axonal projection neurons such as retinal ganglion cells, which are vulnerable to age-related neurodegenerative diseases including Alzheimer's disease.
Brain Res Mol Brain Res 1997 Oct 15
PMID:Retinal Muller glia secrete apolipoproteins E and J which are efficiently assembled into lipoprotein particles. 940 25

The K-variant of butyrylcholinesterase (BCHE-K) recently has been reported to be associated with Alzheimer disease (AD) in carriers of the epsilon4 allele of the apolipoprotein E (APOE) gene. We have re-examined the frequency of the BCHE-K allele in a large data set of both sporadic and familial cases of AD disease, and we have also examined the segregation of three genetic markers on chromosome 3 near BCHE . Our data neither support an association of BCHE-K with sporadic or familial AD, nor do they suggest the existence of another gene nearby on chromosome 3 as a common cause of familial AD.
Hum Mol Genet 1998 May
PMID:Analysis of the butyrylcholinesterase gene and nearby chromosome 3 markers in Alzheimer disease. 953 99


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