Biomedical subjects

Nenad Bogdanovic

Publications and source records attributed to Nenad Bogdanovic.

29 records · Page 2Linked to original sources

PubMed2003

Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.

24S-hydroxycholesterol is a side-chain oxidized oxysterol formed in the brain that is continuously crossing the blood-brain barrier to reach the circulation. There may be an opposite flux of 27-hydroxycholesterol, which is formed to a lower extent in the brain than in most other organs. Here we measured cholesterol, lathosterol, 24S- and 27-hydroxycholesterol, and plant sterols in four different brain areas of deceased Alzheimer's disease (AD) patients and controls. 24S-hydroxycholesterol was decreased and 27-hydroxycholesterol increased in all the brain samples from the AD patients. The difference was statistically significant in four of the eight comparisons. The ratio of 27-hydroxycholesterol to 24S-hydroxycholesterol was significantly increased in all brain areas of the AD patients and also in the brains of aged mice expressing the Swedish Alzheimer mutation APP751. Cholesterol 24S-hydroxylase and 27-hydroxylase protein was not significantly different between AD patients and controls. A high correlation was observed between the levels of 24S-hydroxycholesterol and lathosterol in the frontal cortex of the AD patients but not in the controls. Most probably the high levels of 27-hydroxycholesterol are due to increased influx of this steroid over the blood-brain barrier and the lower levels of 24S-hydroxycholesterol to decreased production. The high correlation between lathosterol and 24-hydroxycholesterol is consistent with a close coupling between synthesis and metabolism of cholesterol in the frontal cortex of the AD brain.

Aged↗

PubMed2003

Amyloid precursor protein carboxy-terminal fragments modulate G-proteins and adenylate cyclase activity in Alzheimer's disease brain.

The influence of three C-terminal sequences and of transmembrane domain from amyloid precursor protein (APP) on the activity of G-proteins and of the coupled cAMP-signalling system in the postmortem Alzheimer's disease (AD) and age-matched control brains was compared. 10 microM APP(639-648)-APP(657-676) (PEP1) causes a fivefold stimulation in the [35S]GTPgammaS-binding to control hippocampal G-proteins. APP(657-676) (PEP2) and APP(639-648) (PEP4) showed less pronounced stimulation whereas cytosolic APP(649-669) (PEP3) showed no regulatory activity in the [35S]GTPgammaS-binding. PEP1 also showed 1.4-fold stimulatory effect of on the high-affinity GTPase and adenylate cyclase activity in control membranes, whereas in AD hippocampal membranes the stimulatory effect of PEP1 was substantially weaker. The PEP1 stimulation of the [35S]GTPgammaS-binding to the control membranes was significantly reduced by 1.5 mM glutathione, 0.5 mM antioxidant N-acetylcysteine and, in the greatest extent, by 0.01 mM of desferrioxamine. In AD hippocampus these antioxidants revealed no remarkable reducing effect on PEP1-induced stimulation. Our results suggest that C-terminal and transmembrane APP sequences possess receptor-like G-protein activating function in human hippocampus and that abnormalities of this function contribute to AD progression. The stimulatory action of these sequences on G-protein mediated signalling suggests the region-specific formation of reactive species.

Acetylcysteine↗

PubMed2003

Auditory peripheral influences on calcium binding protein immunoreactivity in the cochlear nucleus during aging in the C57BL/6J mouse.

The C57BL/6J (C57) mouse was selected as a suitable model for early presbyacusis to determine if there were correlations between peripheral pathology (spiral ganglion loss, inner and outer hair cell loss) and calcium binding immunoreactivity in the cochlear nucleus during aging. The quantitative stereological method, the optical fractionator, was used for determining the total number of neurons and calcium binding immunopositive neurons (calbindin, parvalbumin and calretinin) during aging in the posteroventral- and dorsal cochlear nucleus (PVCN and DCN) in C57 mice. Comparing 30-month-old to 1-month-old C57 mice, a percent increase in parvalbumin and calbindin immunoreactivity was evident in both the PVCN and DCN. Correlations were made between peripheral pathology (spiral ganglion and inner and outer hair cell loss) and calcium binding protein expression. Significant correlations between cochlear pathology and the percentage of parvalbumin and calretinin immunoreactive neurons were demonstrated in the DCN. Moreover, significant correlations were found between cochlear pathology and parvalbumin and calbindin in the PVCN. In summary, the findings imply that degenerative changes in the auditory periphery can modulate neuronal homeostasis by increasing calcium binding proteins in the PVCN and DCN during aging. Taken together, these findings suggest a role for calcium binding proteins in protecting against age-induced calcium toxicity.

Aging↗

PubMed2003

The changing number of cells in the human fetal forebrain and its subdivisions: a stereological analysis.

The total number of cells--including both neurons and glial cells - was estimated in the neocortical part of the human fetal telencephalon in 22 normal brains within four major developmental zones: the cortical plate/marginal zone, the subplate, the intermediate zone and the ventricular/subventricular zone. The fetal ages ranged from 13 to 41 weeks of gestation. The cellular growth in the human fetal forebrain appears to be two-phased: one rapid, exponential phase from 13 to 20 weeks of gestation and a second and slower phase, which increases linearly, from approximately 22 weeks of gestation to term. From 13 to 20 weeks of gestation the total number of cells increases by a factor of 4.3 from 3 x 10(9) cells to 13 x 10(9) cells at 20 weeks of gestation. From mid-gestation to term, the total cell number increases by a factor of 2.9 to 38 x 10(9) cells in the newborn infant. Studying cellular growth in the normal human fetal brain is important since it may serve as a useful parameter for the assessment of cortical growth in non-invasive and histological studies, and thus improve the analysis of fetal brain disturbances.

Autopsy↗

PubMed2003

Molecular identification of AMY, an Alzheimer disease amyloid-associated protein.

One of the neuropathological lesions characteristic of Alzheimer disease (AD) is the cerebral accumulation of the amyloid beta-peptide (A beta). Although numerous studies have demonstrated that A beta spontaneously forms amyloid in vitro, the molecular events underlying A beta amyloid formation in vivo are less well understood. Immunohistochemical studies have shown that other proteins colocalize with A beta in amyloid deposits in brain. The identity of one of these proteins, AMY, has so far remained elusive; therefore we attempted to purify AMY. The AMY protein was found to co-purify with A beta in insoluble fractions from human AD brain, and was absent in brains from control subjects. AMY immunoreactivity was primarily restricted to a 50-kDa and 100-kDa protein species. Interestingly, the chromatographic and immunological profile of AMY resembled the recently identified amyloid-associated protein CLAC, derived from a transmembrane collagen-like precursor, CLAC-P. Antibodies against AMY recognized CLAC-P expressed in mammalian cells. In addition, side-by-side comparisons of AD brain sections and extracts, using antibodies against both AMY and CLAC, respectively, resulted in almost identical staining patterns. Therefore, we conclude that the AMY immunoreactivity seen in association with amyloid in AD brain is due to the presence of the CLAC protein.

Aged↗

PubMed2002

Regulation of the frontocortical sodium pump by Na+ in Alzheimer's disease: difference from the age-matched control but similarity to the rat model.

The Na+ and K+ dependence of the frontocortical Na,K-ATPase in Alzheimer's disease (AD) was compared with that in human control (Co) and rat AD model. In AD, the relationship between the Na/K ratio and the Na,K-ATPase activity showed noticeable left-shift with three-fold increase in the enzyme affinity for Na+ (K(0.5)=10 and 30 mM in AD and Co, respectively). The Na+ dependence of the enzyme in AD showed two different Hill coefficients (n(H)), 1.1 and 0.3, whereas the Co value of n(H) was higher (1.4). The rat AD model generated by ibotenic acid revealed a Na+ dependence similar to AD. The K+ dependence of the Na,K-ATPase showed no significant difference in AD and Co. Compared with Co, AD produced a shift in the break of the Na,K-ATPase Arrhenius plot, suggesting remarkable alterations in the enzyme lipid environment. Our findings support the hypothesis that dysfunction of the Na,K-ATPase in AD is provoked by altered Na+ dependence of the enzyme. An impairment of the pump functionality might serve as an early mechanism of AD that should be interrupted by selective pharmacological agents.

Age Factors↗

PubMed2002

Excitotoxic neurodegeneration induced by intranasal administration of kainic acid in C57BL/6 mice.

Glutamate excitotoxicity plays a key role in inducing neuronal cell death in many neurological diseases. In mice, administration of kainic acid, an analogue of the excitotoxin glutamate, results in hippocampal cell death and seizures. Kainic-acid-induced seizures in mice provide a well-characterized model for studies of human neurodegenerative diseases. However, C57BL/6 mice, which are often used for genetic analyses and transgenic and knockout studies, are resistant to excitotoxicity induced by subcutaneous administration of kainic acid. In the present study, kainic acid administered by the intranasal route was shown to result in continuous tonic-clonic seizures in C57BL/6 mice. These seizures continued for 1-5 h and successfully induced selective lesions in area CA3 of the hippocampus. The survival rate was high even after mice experienced severe seizures. The hippocampal lesions were associated with a high level of cyclooxygenase-2 production as well as astrogliosis. Administration of kainic acid also altered behavioral responses, with mice showing a significant increase in locomotion and rearing activity as indicated by an open-field test. This animal model could provide a valuable tool for exploring the role of excitotoxicity in neuropathological conditions and should be further evaluated in gene-targeting studies of neurodegenerative diseases.

Administration, Intranasal↗

PubMed2002

Postmortem MRI and histopathology of white matter changes in Alzheimer brains. A quantitative, comparative study.

To evaluate whether magnetic resonance imaging (MRI) of white matter changes in Alzheimer's disease either under- or overestimates the findings on neuropathology. Postmortem MRI and neuropathological examination were performed on 6 brains from elderly individuals with a postmortem diagnosis of AD. Using a specially designed brain slicer, the brains were cut corresponding to the MRI images, and stained by Luxol Fast Blue. Quantitative analysis of white matter changes on MRI and neuropathology was performed using stereological principles. Measures from MRI and pathology were highly correlated (r(2) = 0.71). However, pathology showed significantly more extensive changes than did MRI in all cases, with a mean of 54% larger areas. The lesions not identified with MRI represented, however, only minor changes with lower intensity of myelin staining and with an accentuation of the distance between fibres but with preserved axonal network and glial cell density.

Aged↗

PubMed2001

The number of neurons in the inferior olivary nucleus in Alzheimer's disease and normal aging: A stereological study using the optical fractionator.

The nuclei of the olivary complex are involved in regulating motor movements and in motor learning. Aging is characterized by a progressive accumulation of lipofuscin while the number of olivary neurons is unchanged. It is not known whether neuronal loss occurs in the olivary nucleus during Alzheimer's disease (AD). The aim of this study was to estimate the total number of neurons in the principal olivary nucleus (PO) in AD and control brains using an optimized design for sampling and an unbiased stereological method called the optical fractionator. This study was based on 13 control (mean age =57 y, range 17-95 y) and 16 AD brains (mean age = 86 y, range 67-93 y). Using paraffin-embedded, Nissl-stained sections for quantification, we found a significant difference between the mean values (mean+/-SD) of the AD group vs. aged-matched controls (4.3x10^5+/-1.1 vs. 6.53x10^5+/-1.39 p<0,003). There was no significant difference between younger controls vs. older controls (7.1x10^5+/-1.5 vs. 6.5x10^5+/-1.4 p=0.76). While there was no neuronal loss in normal aging, in AD the PO is characterized by a significant neuronal loss up to 34%. can occur in regions devoid of neurofibrillary changes.

Journal Article↗

PubMedDate not supplied

Alive another day.

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Aging↗

PubMedDate not supplied

Association of refractory complex partial seizures with a polymorphism of ApoE genotype.

Apolipoprotein E (ApoE) is a constituent of many types of lipoproteins that play a role in metabolism of cholesterol and lipids in the body as well as in the brain. ApoE is synthesised in astrocytes and microglia and enter to neurons through LDL, LRP and VLDL receptors. Recently it was shown that ApoE is also produced in neurons. ApoE has a role in modulating learning and memory, structural plasticity, mobilization of cholesterol in repair, growth and maintenance of myelin and neuronal membranes during development and aging, and cell death after ischemic, convulsive, or other type of brain injury. The aim of this research was to investigate the possible association of ApoE gene polymorphism with the development of resistance to pharmacological therapy in patients with partial complex seizures with or without secondary generalization. In this prospective matched-pair controlled study, 60 patients with cryptogenic epilepsy with complex partial seizures, with or without secondary generalization, who have been suffering for five or more years, were studied. The first group comprised 30 patients refractory to the current therapy, while the second group consisted of patients with well-controlled seizures. The refractory and non-refractory groups of patients differed significantly in their phenotypes. Phenotype E3/4 was six times more frequent in refractory group than among non-refractory group. The lack of response was shown to be significantly associated with the presence of epsilon4 allele. This study provided evidence that the presence of epsilon4 allele is more often associated with a lack of response to current antiepileptic drugs as compared to epsilon2 and epsilon3 alleles.

Anticonvulsants↗