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Biomedical subjects

A Kenessey

Publications and source records attributed to A Kenessey.

At least 19 recordsLinked to original sources
PubMed1995

Detection of D-aspartate in tau proteins associated with Alzheimer paired helical filaments.

Paired helical filaments (PHF) characteristic of Alzheimer neurofibrillary lesions are known to contain a modified form of microtubule associated protein tau. These proteins, PHF-tau, differ from normal tau in the extent and the site of phosphorylation. To determine whether PHF-tau, tau proteins from normal adult brains (N-tau), tau proteins from Alzheimer brains not associated with PHF (A-tau), and tau proteins from fetal brains (F-tau) differ in racemization, these proteins were compared for their D-aspartate content. The results demonstrated that PHF-tau contain more D-aspartate than N-tau, A-tau and F-tau. The average percentage D-aspartate for these proteins, after a correction for background, are 4.9%, 2.8%, 1.6%, and 1% for PHF-tau, N-tau, A-tau and F-tau, respectively. It remains to be determined if the increase in D-aspartate is a consequence of PHF formation. It is also unknown if the change in D-aspartate content in PHF-tau is associated with phosphorylation, which alters the susceptibility of tau to proteolysis.

Alzheimer Disease↗
PubMed1995

The distribution and biochemical properties of a Cdc2-related kinase, KKIALRE, in normal and Alzheimer brains.

The biochemical properties and distribution of a Cdc2-related kinase, KKIALRE, were studied in brain tissues and cultured cells with antibodies to a subregion of KKIALRE protein deduced from cDNA. In adult human brain, the KKIALRE-immunoreactive protein consisted of four or five isoforms having a molecular size of 40-52 kDa, whereas in fetal brain, there was one protein of approximately 48 kDa. Cultured astrocytes, neuroblastoma cells, and mouse brains contained the fetal form of KKIALRE protein. KKIALRE-immunoreactive proteins were capable of phosphorylating histone and synthetic peptides with the X-Ser-Pro-X motif, indicating that these proteins belong to the proline-directed Ser/Thr protein kinase family. The KKIALRE immunoreactivity was detected primarily in fibrous astrocytes in white matter and perivascular and subpial spaces, as well as in Bergmann glia in the cerebellum. In fetal brains radial glia were weakly immunoreactive. Reactive astrocytes were more intensely labeled than other glia. Neurons in normal brains and brains with Alzheimer's disease (AD) displayed no KKIALRE immunoreactivity. KKIALRE immunoreactivity was similar in neurons with and without neurofibrillary tangles. The results indicate that in CNS, the KKIALRE protein is mainly a glial protein that is up-regulated in gliosis and that it probably plays no role in the hyperphosphorylation of tau in AD brains.

Adult↗
PubMed1993

The extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filaments.

The relationship between Alzheimer's disease (AD) and expression of fetal proteins was examined by: (i) determining the phosphate content of tau prepared from fetal brains (F-tau); (ii) comparing F-tau, tau from normal adult human brains (N-tau) and tau from paired helical filaments in AD brains (PHF-tau) for phosphate content; and (iii) testing the reactivity of F-tau with five antibodies known to recognize PHF-tau. The antibodies have been reported to recognize phosphate dependent epitopes at the carboxy-terminal half of the tau molecule. Our data shows that on the average, F-tau contains 7 mol phosphate/mol protein, which is comparable to the phosphate content of PHF-tau, but is 3-4 times higher than that of N-tau. Immunoblotting shows that all of the tested antibodies reacted with F-tau on immunoblots, indicating that F-tau and PHF-tau are phosphorylated at similar sites. A difference between PHF-tau and F-tau is the state of phosphorylation in the Tau-1 epitope, an epitope reactive with a monoclonal anti-tau antibody, Tau-1. This epitope, which is phosphorylated in all PHF-tau, is phosphorylated only in some of the F-tau. The sharing of phosphorylated sites between F-tau and PHF-tau has also been reported by others in studies with antibodies to different and similar phosphorylated epitopes. Together these observations indicate that the extent and the site of phosphorylation in F-tau and PHF-tau tau are similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Abortion, Spontaneous↗
PubMed1992

The distribution of cathepsin D activity in adult and aging human brain regions.

We measured the activity of cathepsin D, the major cerebral protease, in 50 separate areas of the central nervous system of adult and aged humans, using hemoglobin as the substrate. The activity showed significant regional heterogeneity, with average differences of 50-100% between the lower and higher level areas, and a more than threefold difference between the lowest and highest levels. The forebrain, midbrain, and hindbrain each had areas of high and low activity; cerebellum and cord areas were among those with low activity. Cathepsin levels tended to increase with age in about half of the areas analyzed, and the increases were significant in 14. Statistically significant decreases with aging were observed in two areas. The increases varied between 30 and 60%, and the decreases were 20%. Enzyme activity in thalamus, hypothalamus, pons, medulla, and cerebellum increased with age. In the ventrolateral medulla, which contains the major portion of the cerebral noradrenergic cells, the cathepsin D levels increased with age; in the dorsal raphe area, which contains the major portion of the cerebral serotonergic cells, the enzyme levels decreased. The change with age in human brain seems to be less than what we observed in rat brain, where activity more than doubled in most areas. The changes in enzyme levels need to be tested at more ages to establish a pattern of changes in activity throughout life.

Adult↗
PubMed1991

Effects of brief starvation on brain protease activity.

Changes in the activity of proteases (cathepsin D and calpains) caused by 48-h food withdrawal were studied in the brain, liver, kidney, spleen, and heart of 3-, 12-, and 24-month-old Fischer rats. Cathepsin D activity was similar in brain, liver, and heart of control animals; in kidney it was 5-fold higher and in spleen about 10-fold higher. With age, activity increased in all organs tested except spleen. Brief starvation caused no change of cathepsin D activity in brain, but caused an increase in liver and a decrease in spleen. Neutral proteolytic activity in control was highest in the pons-medulla-cerebellum fraction of brain, and activity in liver and heart was below that in brain. Activity increased with age in brain and decreased in other organs. Brief starvation in young animals caused an increase in activity in brain, and a decrease in liver and spleen. Isolated calpain II activity was high in control brain. It increased with age in the cerebrum. Brief starvation resulted in a decrease in the brain. The results indicate that the protease content of the brain is altered with age and in malnutrition, with changes not being the same for all proteases, and changes in brain being different from those in other organs.

Aging↗
PubMed1990

Calpain II activity and calpastatin content in brain regions of 3- and 24-month-old rats.

In previous studies, we found a significantly higher (100% or more) content of cathepsin D in the aging brain. In the present study, we determined activity of Ca2(+)-activated neutral protease requiring millimolar Ca2+ (calpain II, CANP II) and amount of its endogenous inhibitor, calpastatin, in extracts of various brain regions of 3-month-old and 24-month-old male Fischer-344 rats. Calpain II was separated from calpastatin in a single step (chromatography) and its activity was tested using as substrates [methyl-14C]alpha-casein, the cytoskeletal proteins desmin and actin, and a mixture of neurofilament triplet proteins and glial fibrillary acidic proteins (GFAP). We found no changes in calpain II activity in pons-medulla and spinal cord, but significant increases were detected in cortex (72%) and striatum (63%) of the 24-month-old rats using [methyl-14C]alpha-casein as substrate. The profile of desmin and actin breakdown showed regional variations somewhat different from those of [methyl-14C]alpha-casein. With desmin, the greatest increases with age were in the striatum (82%) and hypothalamus (46%), but there were no alterations in cortex, cerebellum, and pons-medulla. With actin, slightly enhanced activity in cortex and cerebellum was noticeable. Calpastatin content in brain regions was also increased, with the regional pattern of increase fairly similar to the pattern of enzyme activity increase. The causes and the physiological consequences of increased calpain and calpastatin content in the aged brain are being investigated. That changes with age are somewhat different with the various brain protein substrates indicates that some of the properties of the enzyme also undergo alteration with age.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1989

Increase in cathepsin D activity in rat brain in aging.

Cathepsin D-like activity in homogenates of five brain areas of 3-month-old and 24-month-old Fischer 344 rats was measured. With hemoglobin as substrate at pH 3.2, more than 90% of the activity was inhibited by pepstatin. In each area studied, activity was more than twice as high in the old rat brain: 140-160% higher in the cortex, cerebellum, pons-medulla, and striatum and 90-100% higher in the hippocampus and spinal cord. The greatly increased metabolic capacity in the absence of an increase in protein turnover may have a role in age-related pathological degeneration in the brain.

Aging↗
PubMed1987

Interaction of 2,3-benzodiazepines with peripheral benzodiazepine receptors.

2,3-Benzodiazepines (BZs), such as tofizopam (TP) and GYKI-51 189 have anxiolytic potency accompanied by moderate sedative action, but no anticonvulsant and muscle relaxant activities. These compounds show relatively low affinity to the peripheral benzodiazepine (PBZ) receptors, nevertheless, they decrease the binding of (3H)Ro5-4864 to its receptors in heart, kidney and brain membranes. This diminution in the binding is due to a decrease in the affinity for the ligand (Kd) without any change in the maximal number of binding sites (Bmax). This interaction of 2,3-BZs with PBZ binding sites may explain their pharmacological profile.

Animals↗
PubMed1987

Neuropharmacology of a new psychotropic 2,3-benzodiazepine.

1-(3-Chlorophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 51189) is a new analogue of tofisopam. Due to the novel chemical structure this molecule displays a peculiar spectrum of pharmacological activity. In many respects tofisopam and its new analogue differ from the traditional 1,4-benzodiazepines, e.g. in that they possess selective anxiolytic action without muscle relaxant and anticonvulsive activity, as well as they do not show any affinity for the 1,4-benzodiazepine receptors. This new compound exerts more pronounced anxiolytic potency than tofisopam. In addition to its main action it possesses significant antidepressant activity. It attenuates psychomotor agitation and exerts significant antiaggressive effect by reducing both spontaneous and induced aggressiveness. Vegetative responses (rise in blood pressure and heart rate) induced by electric stimulation of the hypothalamus are also inhibited by this compound, while motor functions remain unaffected and no somnolence is induced. The new tofisopam analogue fails to exert any potentiating effect either on ethanol or on barbiturates. GYKI-51189 has a highly favourable therapeutic index and only few side effects. Neither tolerance nor dependence was observed during the chronic toxicological investigations.

Aggression↗
PubMed1984

Interaction of calcium channel blockers with non-neuronal benzodiazepine binding sites.

The ability of calcium channel blockers to displace the binding of benzodiazepine ligands was investigated in rat heart, kidney, and brain. The dihydropyridine calcium channel blockers nifedipine and nitrendipine displaced the binding of the non-neuronal-site ligand [3H]Ro5-4864, but not that of the neuronal-site ligands [3H]flurazepam or [3H]clonazepam. The inhibition was competitive, with Ki values in the micromolar range. Other calcium channel blockers--i.e., verapamil and diltiazem--were inactive at both sites. Thus, non-neuronal benzodiazepines bind to a class of sites that also binds dihydropyridines. This implies a role for benzodiazepines in the mediation of calcium-dependent phenomena.

Animals↗