Apolipoprotein E-epsilon 4 allele and Alzheimer's disease.
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Age Factors↗
Biomedical subjects
M E Cheetham
Publications and source records attributed to M E Cheetham.
Expression of alternatively-spliced glutamate receptors in human hippocampus.
Rat glutamate receptors have been shown to be expressed as two developmentally regulated, alternatively spliced isoforms. We have investigated the expression of these isoforms of GluRA and GluRB in the human hippocampus. The expression pattern of the mRNAs coding for these subunits does not correspond to that in the rat hippocampus, both isoforms being preferentially expressed in the dentate gyrus and CA1 regions, with lower expression in CA3, with the exception of GluRB flop, where hybridization in CA3 is only lower than in dentate gyrus. Cloning of cDNA from human frontal cortex has also revealed that the two isoforms of human GluRB have virtual nucleotide sequence identity with the alternative exons in the rat, confirming the usefulness of oligonucleotides complementary to the rat cDNAs as probes for these receptor subunits in human neuropsychiatric disorders.
Alternative Splicing↗
Investigation of the changes in neuronal distribution and phosphorylation state of MAP1X during development.
Neurite outgrowth is dependent on the presence in neurites of assembled microtubules which consist of polymerized tubulin to which microtubule-associated proteins (MAPs) are bound. This study adds to previous evidence of the similarity between the high molecular weight MAPs, MAP1X, MAP1B and MAP5, and explains the different staining patterns observed by different laboratories on frozen sections, using monoclonal antibodies against each MAP. Previous studies have shown that monoclonal antibody (mAb) G10 binds to MAP1X and labels growing but not mature axons in the rat nervous system and, therefore, expression of this MAP or molecular changes in it may be important for axon growth. It has been shown that a phosphorylated form of MAP5 can be detected by SDS-PAGE in brain areas with growing axons. This study shows that there is phosphate dependency of mAbG10 binding to MAP1X which is, however, lost during brain homogenization.
Aging↗
Human homologues of the bacterial heat-shock protein DnaJ are preferentially expressed in neurons.
The bacterial heat-shock protein DnaJ has been implicated in protein folding and protein complex dissociation. The DnaJ protein interacts with the prokaryotic analogue of Hsp70, DnaK, and accelerates the rate of ATP hydrolysis by DnaK. Several yeast homologues of DnaJ, with different proposed subcellular localizations and functions, have recently been isolated and are the only eukaryotic forms of DnaJ so far described. We have isolated cDNAs corresponding to two alternatively spliced transcripts of a novel human gene, HSJ1, which show sequence similarity to the bacterial DnaJ protein and the yeast homologues. The cDNA clones were isolated from a human brain-frontal-cortex expression library screened with a polyclonal antiserum raised to paired-helical-filament (PHF) proteins isolated from extracts of the brains of patients suffering from Alzheimer's disease. The similarity between the predicted human protein sequences and the bacterial and yeast proteins is highest at the N-termini, this region also shows a limited similarity to viral T-antigens and is a possible common motif involved in the interaction with DnaK/Hsp70. Northern-blot analysis has shown that human brain contains higher levels of mRNA for the DnaJ homologue than other tissues examined, and hybridization studies with riboprobes in situ show a restricted pattern of expression of the mRNA within the brain, with neuronal layers giving the strongest signal. These findings suggest that the DnaJ-DnaK (Hsp70) interaction is general to eukaryotes and, indeed, to higher organisms.
Amino Acid Sequence↗
The responses of the catecholamines and beta-endorphin to brief maximal exercise in man.
The responses to brief maximal exercise of 10 male subjects have been studied. During 30 s of exercise on a non-motorized treadmill, the mean power output (mean +/- SD) was 424.8 +/- 41.9 W, peak power 653.3 +/- 103.0 W and the distance covered was 167.3 +/- 9.7 m. In response to the exercise blood lactate concentrations increased from 0.60 +/- 0.26 to 13.46 +/- 1.71 mmol.l-1 (p less than 0.001) and blood glucose concentrations from 4.25 +/- 0.45 to 5.59 +/- 0.67 mmol.l-1 (p less than 0.001). The severe nature of the exercise is indicated by the fall in blood pH from 7.38 +/- 0.02 to 7.16 +/- 0.07 (p less than 0.001) and the estimated decrease in plasma volume of 11.5 +/- 3.4% (p less than 0.001). The plasma catecholamine concentrations increased from 2.2 +/- 0.6 to 13.4 +/- 6.4 nmol.l-1 (p less than 0.001) and 0.2 +/- 0.2 to 1.4 +/- 0.6 nmol.l-1 (p less than 0.001) for noradrenaline (NA) and adrenaline (AD) respectively. The plasma concentration of the opioid beta-endorphin increased in response to the exercise from less than 5.0 to 10.2 +/- 3.9 p mol.l-1. The post-exercise AD concentrations correlated with those for lactate as well as with changes in pH and the decrease in plasma volume. Post-exercise beta-endorphin levels correlated with the peak speed attained during the sprint and the subjects peak power to weight ratio. These results suggest that the increases in plasma adrenaline are related to those factors that reflect the stress of the exercise and the contribution of anaerobic metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Isolation of cDNAs coding for epitopes shared by microtubule-associated proteins and neurofibrillary tangle in Alzheimer's disease.
5 cross-hybridizing cDNA clones of sizes 2.2 (3 cDNAs), 1.3 and 0.8 kb corresponding to tau microtubule-associated protein have been isolated from a rat brain lambda gt11 expression library. Antibodies affinity-purified using the fusion protein encoded by the cDNAs were observed to label tau polypeptides on Western blots and Alzheimer's neurofibrillary tangles.
Alzheimer Disease↗
High intensity training and treadmill sprint performance.
Twelve county standard hockey players completed a 30 second sprint on a non-motorised treadmill and an uphill treadmill running test to determine maximum oxygen uptake (VO2 max) before and after 6 weeks of high intensity training (fast runs 3-5 miles, intervals 30-300 m and circuit training), whilst 11 club standard players completed the same tests without any additional training. For the county standard group there was an 11.1% and 5.0% improvement in peak running speed and distance covered on the sprint treadmill respectively, a 4.2% improvement in VO2 max and an 11.5% improvement in run time to exhaustion during the VO2 max test (all p less than 0.01). No changes were observed for the club standard group. There were large increases in blood lactate (county group 13.26 +/- 1.83 mM) and blood glucose (county group 1.56 +/- 0.71 mM) concentrations as a result of the treadmill sprint, but there were no additional changes in these variables as a result of training. Thus, the mechanism of adaptation in this type of brief maximal exercise remains in question.
Adult↗
Human muscle metabolism during sprint running.
Biopsy samples were obtained from vastus lateralis of eight female subjects before and after a maximal 30-s sprint on a nonmotorized treadmill and were analyzed for glycogen, phosphagens, and glycolytic intermediates. Peak power output averaged 534.4 +/- 85.0 W and was decreased by 50 +/- 10% at the end of the sprint. Glycogen, phosphocreatine, and ATP were decreased by 25, 64, and 37%, respectively. The glycolytic intermediates above phosphofructokinase increased approximately 13-fold, whereas fructose 1,6-diphosphate and triose phosphates only increased 4- and 2-fold. Muscle pyruvate and lactate were increased 19 and 29 times. After 3 min recovery, blood pH was decreased by 0.24 units and plasma epinephrine and norepinephrine increased from 0.3 +/- 0.2 nmol/l and 2.7 +/- 0.8 nmol/l at rest to 1.3 +/- 0.8 nmol/l and 11.7 +/- 6.6 nmol/l. A significant correlation was found between the changes in plasma catecholamines and estimated ATP production from glycolysis (norepinephrine, glycolysis r = 0.78, P less than 0.05; epinephrine, glycolysis r = 0.75, P less than 0.05) and between postexercise capillary lactate and muscle lactate concentrations (r = 0.82, P less than 0.05). The study demonstrated that a significant reduction in ATP occurs during maximal dynamic exercise in humans. The marked metabolic changes caused by the treadmill sprint and its close simulation of free running makes it a valuable test for examining the factors that limit performance and the etiology of fatigue during brief maximal exercise.
Adult↗
A laboratory running test: metabolic responses of sprint and endurance trained athletes.
A laboratory-based sprint running test has been devised to examine the performance characteristics and metabolic responses of an individual to 30 seconds of maximal exercise. A non-motorised treadmill was used so that the individual was able to sprint at his own chosen speed and also to vary his speed as fatigue occurred. The treadmill was instrumented so that the chosen speeds as well as the equivalent distance travelled could be monitored by micro-computer throughout the test. The test-retest reliability of the procedure was investigated with 14 recreational runners who performed the test on different days. A good correlation (r = 0.93) was found between the values obtained for peak running speeds on the two occasions. In an attempt to establish whether or not this test could be used to identify the differences in the performance characteristics of highly trained individuals, the responses to the test of eleven sprint trained and eleven endurance trained athletes were examined. The sprint trained athletes covered a greater distance (162.2 +/- 5.95 m vis 153.51 +/- 12.32 m; p less than 0.01) and had higher blood lactate concentrations (16.52 +/- 1.23 mM vis 12.98 +/- 1.77 mM; p less than 0.01) than the endurance trained athletes. Therefore this laboratory sprint running test offers an additional way of investigating human responses to brief periods of high intensity exercise.
Adult↗