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Biomedical subjects

Bengt Winblad

Publications and source records attributed to Bengt Winblad.

At least 55 records · Page 3Linked to original sources
PubMed2005

Polychlorinated biphenyls alter expression of alpha-synuclein, synaptophysin and parkin in the rat brain.

Polychlorinated Biphenyls (PCBs)-induced changes in synaptic transmission are one of the effects of their neurotoxicity but the mechanism remains unknown. We assessed the in vivo effects of the PCBs mixture, Aroclor 1254 on the expression of neuronal proteins that are involved in the synaptic function and/or are associated with neurodegeneration. Wistar rats were treated orally with repeated doses of Aroclor 1254 and the levels of soluble alpha-synuclein, parkin, synaptophysin and amyloid precursor protein (APP) in the brain were determined by Western blotting. The results showed that Aroclor did not cause changes in the expression and processing of APP but at a dose 100 microg/g/day repeated for 6 days caused a decrease in the expression of alpha-synuclein in the cerebellum, cortex, hippocampus and hypothalamus of the animals sacrificed 2 days after treatment. The decrease in alpha-synuclein was accompanied by a transient increase in parkin and synaptophysin levels. Interestingly, in the hypothalamus the levels of alpha-synuclein remained decreased after 21 days post treatment perhaps due to regional differences in the PCBs elimination or perhaps a more specific interaction with the dopaminergic cells that are present in the hypothalamus that needs to be investigated further.

Amyloid beta-Peptides↗
PubMed2005

Cognitive impairment is the major risk factor for development of geriatric syndromes during hospitalization: results from the GIFA study.

OBJECTIVE: To detect the main factors associated with the occurrence of specific geriatric syndromes (namely pressure sores, fecal incontinence, urinary incontinence and falls) in elderly patients during hospitalization. DESIGN: Observational prospective study. SETTING: Eighty-one community and university hospitals throughout Italy. PARTICIPANTS: 13,729 patients aged 65 years and more, consecutively admitted to medical or geriatric acute wards during 20 months in the period between 1991 and 1998. MEASUREMENTS: Occurrence of pressure sores, fecal incontinence, urinary incontinence and falls during the stay in hospital. RESULTS: Pressure sores were already present in 3% of hospitalized subjects, fecal incontinence in 7.3%, while urinary incontinence, evaluated on a subgroup of total population (4,268 subjects), had a prevalence of 22.3%. During hospitalization (mean stay of 15 days), 74 subjects developed new pressure sores, 55 became fecal and 35 urinary incontinent, and 279 subjects had at least one episode of fall. In multivariate analyses, cognitive impairment, advanced age (85+ years), length of stay (more than 3 weeks) and severe disability were the main independent predictors of development of the four geriatric syndromes, with cognitive impairment as the most significant risk factor for all the four outcomes (OR 4.9, 95% CI 2.4-9.9 for pressure sores; OR 6.3, 95% CI 3.0-13.0 for fecal incontinence; OR 5.3, 95% CI 2.3-12.0 for urinary incontinence; OR 1.6, 95% CI 1.2-2.3 for falls). CONCLUSION: Very old people have a significant increased risk of several geriatric syndromes during the stay in hospital, particularly if it is long and they are cognitively impaired. A standardized comprehensive geriatric evaluation at admission could be helpful in detecting all subjects at risk and preventing the development of hospital-acquired geriatric syndromes.

Accidental Falls↗
PubMed2005

A nine-transmembrane domain topology for presenilin 1.

Presenilin (PS) provides the catalytic core of the gamma-secretase complex. Gamma-secretase activity leads to generation of the amyloid beta-peptide, a key event implicated in the pathogenesis of Alzheimer disease. PS has ten hydrophobic regions, which can all theoretically form membrane-spanning domains. Various topology models have been proposed, and the prevalent view holds that PS has an eight-transmembrane (TM) domain organization; however, the precise topology has not been unequivocally determined. Previous topological studies are based on non-functional truncated variants of PS proteins fused to reporter domains, or immunocytochemical staining. In this study, we used a more subtle N-linked glycosylation scanning approach, which allowed us to assess the topology of functional PS1 molecules. Glycosylation acceptor sequences were introduced into full-length human PS1, and the results showed that the first hydrophilic loop is oriented toward the lumen of the endoplasmic reticulum, whereas the N terminus and large hydrophilic loop are in the cytosol. Although this is in accordance with most current models, our data unexpectedly revealed that the C terminus localized to the luminal side of the endoplasmic reticulum. Additional studies on the glycosylation pattern after TM domain deletions, combined with computer-based TM protein topology predictions and biotinylation assays of different PS1 mutants, led us to conclude that PS1 has nine TM domains and that the C terminus locates to the lumen/extracellular space.

Amino Acid Sequence↗
PubMed2005

Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms.

Abnormal phosphorylation of microtubule-associated protein tau plays a critical role in Alzheimer's disease (AD), together with a distinct decrease of energy metabolism in the affected brain regions. To explore the effect of acute energy crisis on tau phosphorylation and the underlying mechanisms, we incubated rat brain slices in artificial cerebrospinal fluid (aCSF) at 37 degrees C with or without an oxygen supply, or in aCSF with low glucose concentrations. Then, the levels of total, phosphorylated and unphosphorylated tau, as well as the activities and levels of protein phosphatase (PP)-1, PP-2A, glycogen synthase kinase 3 (GSK-3), extracellular signal-regulated protein kinase (ERK) and C-jun amino terminal kinase (JNK), were measured. It was found, unexpectedly, that tau was significantly dephosphorylated at Ser396/Ser404 (PHF-1), Ser422 (R145), Ser199/Ser202 (Tau-1), Thr181 (AT270), Ser202/Thr205 (AT8) and Thr231 (AT180) by acute anoxia for 30 min or 120 min. The activity of PP-2A and the level of dephosphorylated PP-2A catalytic subunit at tyrosine 307 (Tyr307) were simultaneously increased. The active forms of ERK1/2 and JNK1/2 were decreased under anoxic incubation. The PP-2A inhibitor, okadaic acid (OA, 0.75 microm), completely prevented tau from acute anoxia-induced dephosphorylation and restored the active forms of ERK1/2 and JNK1/2 to the control level. The activities and protein levels of GSK-3 and PP-1 showed no change during acute anoxia. These data suggest that acute anoxia induces tau dephosphorylation, and that PP-2A may play a key role in tau dephosphorylation induced by acute anoxia.

Acute Disease↗
PubMed2005

Zinc induces neurofilament phosphorylation independent of p70 S6 kinase in N2a cells.

Hyperphosphorylated neurofilaments are a part of neurofibrillary tangles in Alzheimer's disease brains. Zinc has been shown to be increased in the brain areas heavily affected by Alzheimer pathologies. Zinc could induce tau hyperphosphorylation in SH-SY5Y and N2a cells, and tau phosphorylation may be mediated by p70 S6 kinase activation. Many of the tau kinases can also phosphorylate neurofilaments, and in this study we wanted to see whether neurofilament phosphorylation is regulated by p70 S6 kinase in N2a cells. We found that zinc induces rapamycin-dependent p70 S6 kinase phosphorylation at Thr421/Ser424 and Thr389, and rapamycin-independent phosphorylation of neurofilaments at the SMI34 epitope. Although zinc could induce cell proliferation and cell growth, and increased phosphorylation of neurofilaments, only cell growth appeared to be related to p7056kinase activation.

Antibiotics, Antineoplastic↗
PubMed2005

Increased microglial activation and astrogliosis after 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, intranasal administration of kainic acid (KA), an analogue of the excitotoxin glutamate, results in hippocampal cell death and provides a well-characterized model for studies of human neurodegenerative diseases. In this study, we describe neurodegeneration and gliosis following intranasal administration of KA in C57BL/6 mice. By using Nissl's staining, neurodegeneration was found in area CA3 of hippocampus, and neuronal apoptosis was demonstrated by enhanced FAS(CD95/APO-1) expression detected by immunohistochemistry and Western blotting. Astrogliosis was exhibited by increased glial fibrillary acidic protein (GFAP) expression in the hippocampus and cortex. We also studied the profile of molecular expression on microglia in C57BL/6 mice. One and 3 days after KA administration, CD45, F4/80, CD86, MHCII, iNOS but not CD40 expression was enhanced or induced on microglia. In summary, KA administration results in an early microglial activation and a prolonged astrogliosis in C57BL/6 mice.

Animals↗
PubMed2005

Alpha-MSH decreases core and brain temperature during global cerebral ischemia in rats.

A key pathological event during cerebral ischemia is the excitotoxic release of glutamate. We have shown previously that alpha-melanocyte-stimulating hormone (alpha-MSH) enhances the hypothermia induced by kainic acid. We have investigated the effects of systemic administration of alpha-MSH on four-vessel occlusion forebrain ischemia on core temperature (CT) and brain temperature (BT), respectively. After 10 min cerebral ischemia, BT was lower in alpha-MSH- than in saline-injected animals. After 10 min reperfusion, both CT and BT were lower than the corresponding pre-ischemic levels after injection of alpha-MSH. alpha-MSH did not influence CT or BT in sham-operated rats. The alpha-MSH-induced hypothermia and its potentiation of reduction in BT during global cerebral ischemia, may contribute to neuroprotective effects of alpha-MSH.

Animals↗
PubMed2005

Zinc-induced anti-apoptotic effects in SH-SY5Y neuroblastoma cells via the extracellular signal-regulated kinase 1/2.

Zinc levels are increased in brain areas severely affected by Alzheimer's disease (AD) pathologies. Zinc has both protective and neurotoxic properties and can stimulate both phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Several kinases related to these pathways including protein kinase B (PKB), p70 S6 kinase (p70S6K), and extracellular signal-regulated kinase 1/2 (ERK1/2) are known cell survival factors and are overactivated in neurons bearing neurofibrillary tangles (NFTs) in AD. The present study aimed to determine whether anti-apoptotic effects of zinc are mediated via these signaling pathways. Zinc was used to treat SH-SY5Y neuroblastoma cells and effects investigated in relation to PKB, p70S6K, and ERK1/2 in the absence and presence of the pro-apoptotic agent staurosporine (STS). Cell damage was evaluated by measuring levels of DNA fragmentation as well as the WST-1 assay for cell viability. Results indicated that: (1) treatment with high doses of zinc (>/=400 microM) for short time periods (</=2 h) gave rise to increased levels of DNA fragments, increased cell membrane permeability, and reduced mitochondria membrane potential; (2) treatment with 100 microM zinc for >2 h reversed an increased DNA fragmentation due to U0126 inhibition of ERK1/2; (3) increased DNA fragmentation due to STS could be protected against by 100 microM zinc; (4) the protective effects of 100 microM zinc on STS-induced DNA fragmentation could be partially reversed by U0126. These results indicate that a zinc-induced anti-apoptotic response in SH-SY5Y cells likely occurs through ERK1/2.

Apoptosis↗
PubMed2005

Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease.

BACKGROUND: Vascular risk factors play a role in the development of dementia, including Alzheimer disease (AD). However, little is known about the effect of body mass index and clustering of vascular risk factors on the development of dementia. OBJECTIVE: To investigate the relation between midlife body mass index and clustering of vascular risk factors and subsequent dementia and AD. DESIGN AND SETTING: Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1449 individuals (73%) aged 65 to 79 years participated in the reexamination in 1998. MAIN OUTCOME MEASURES: Dementia and AD. RESULTS: Obesity at midlife (body mass index>30 kg/m2) was associated with the risk of dementia and AD even after adjusting for sociodemographic variables (odds ratio [OR], 2.4 [95% confidence interval (CI), 1.2-5.1]). The association was somewhat modified by further adjusting for midlife blood pressure, total cholesterol level, and smoking (OR, 2.1 [95% CI, 1.0-4.6]) and also for apolipoprotein E genotype and history of vascular disorders (OR, 1.9 [95% CI, 0.8-4.6]). Midlife obesity, high total cholesterol level, and high systolic blood pressure were all significant risk factors for dementia with ORs of around 2 for each factor, and they increased the risk additively (OR, 6.2 for the combination). CONCLUSIONS: Obesity at midlife is associated with an increased risk of dementia and AD later in life. Clustering of vascular risk factors increases the risk in an additive manner. The role of weight reduction for the prevention of dementia needs to be further investigated.

Age Factors↗
PubMed2005

Biomarkers for apoptosis in Alzheimer's disease.

Alzheimer's disease (AD) affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. Today there is no cure for this devastating and always lethal disease and therefore it is of great interest for patients, relatives and societies to find new drugs that can hinder the disease process. During the progression of AD a substantial amount of neurons degenerate in the brain. The mechanisms of cell death involved in AD have not been fully elucidated. However, there are several reports showing that neurons die partly by apoptosis in the AD brain. Drugs blocking apoptosis could therefore be potentially useful for early prevention of neuronal cell death. Biomarkers for apoptosis should be important tools in the evaluation of drug effects and in the diagnostics of AD. Here we review the current knowledge in the field and discuss potential biomarkers for apoptosis in AD.

Aged↗
PubMed2005

Clinical trials of potential antidepressants: to what extent are the elderly represented: a review.

BACKGROUND: There is widespread use of antidepressants in the elderly population. The principle of treatment of depression, however, is derived mostly from studies employing young adults and healthy elderly. This article reviews the literature on the extent to which the elderly are represented in clinical trials of potential antidepressants. METHOD: Medline search of relevant articles of clinical trials of potential antidepressants. RESULTS: The maximum age of inclusion for most clinical trials was 65 years. The highest age reported for depressed subjects was 90 years. There was no clear consensus on who were considered to be elderly; clinical trials conducted on the elderly included subjects who were 50, 55, or 60 years and over. Pharmacological studies on healthy subjects were most often done on young adults, age range 18 to 65 years. The period of study was relatively shorter for clinical trials done on elderly subjects. There was however, no difference in the exclusion or inclusion criteria between studies done in young and elderly subjects. CONCLUSIONS: Elderly subjects aged 75 years and over were clearly underrepresented in the clinical trials of potential antidepressants. For drugs that are used by the elderly, in its pivotal studies for registration, the inclusion of at least 25% of subjects aged 75 years and over is recommended.

Adult↗
PubMed2005

Cytokine production by a human microglial cell line: effects of beta-amyloid and alpha-melanocyte-stimulating hormone.

Senile plaques in the Alzheimer's disease (AD) are formed by aggregation of beta-amyloid (Abeta) peptide. Abeta peptide has been shown to activate microglia and stimulate their production of inflammatory factors, such as cytokines. In the AD brain, the continued presence of amyloid plaques may keep microglia persistently activated, leading to chronic inflammation in the CNS. It is well established that alpha-melanocyte-stimulating hormone (alpha-MSH) gives rise to anti-inflammatory and anti-pyretic effects. The biological activities of alpha-MSH are mediated by one or more of the melanocortin receptor (MCR) subtypes, i.e. MCR1 - MCR5. The aim of the present study was to determine the effect of alpha-MSH alone and on Abeta-activated microglial cells with regard to the secretion of inflammatory cytokines, such as interleukin-6 (IL-6), and to determine which receptor subtype mediates the effects of alpha-MSH. The human microglial cell line, CHME3, was incubated for 24 h with freshly dissolved Abeta(1-40), interferon-gamma (IFN-gamma) and/or alpha-MSH. Freshly dissolved Abeta(1-40) (5-60 microM) resulted in a dose-dependent decrease in cell viability, along with a dose-dependent increase in IL-6 release. Neither IFN-gamma nor alpha-MSH affected the Abeta-induced secretion of IL-6, but resulted in a dose-dependent increase in basal IL-6 release. Agouti, the endogenous antagonist of MCR1 and 4, further increased the alpha-MSH-induced secretion of IL-6. RT-PCR showed the expression of MCR1, MCR3, MCR4 and MCR5 mRNA. The combined data suggest that the effect of alpha-MSH in increasing IL-6 release from the human microglial cell line is mediated by MCR3 or MCR5.

Agouti Signaling Protein↗
PubMed2005

Transgenic overexpression of interleukin-1 receptor antagonist in the CNS influences behaviour, serum corticosterone and brain monoamines.

The effects of brain-directed overexpression of human soluble interleukin-1 receptor antagonist (hsIL-1ra) on behaviour, serum corticosterone (CST) levels and concentrations of dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites in different brain regions, were investigated in six months old homozygotic transgenic male mice (Tg hsIL-1ra(+/+)). The transgenic and age-matched wild type (WT) mice were subjected to a battery of behavioural tests for analysis of open field (OF) behaviours, anxiety in elevated plus maze (EPM), and motor performance in rotarod. One week after the last behavioural test, half of the mice from each genotype were subjected to a mild stress, while the remaining mice served as controls for the determination of serum CST levels and monoamine concentrations in different brain regions. Tg hsIL-1ra(+/+) mice had higher locomotor scores and showed less habituation in the OF test, spent more time in the open arms of the EPM and had similar motor performance as compared to WT mice. The serum CST levels were comparable, both in basal conditions and upon stress, in the two genotypes. Tg hsIL-1ra(+/+) mice had lower concentrations of DA, 5-HT and their metabolites in several brain regions, with different effects on monoamine turnover upon stress. In conclusion, brain-directed overexpression of hsIL-1ra resulted in increased locomotion and decreased habituation, an anxiolytic effect, but did not influence motor performance. Finally, the activation of hypothalamo-pituitary-adrenal (HPA)-axis was comparable in the two genotypes, however Tg hsIL-1ra(+/+) mice had a modified metabolism of brain monoamines as compared to WT mice.

Animals↗
PubMed2005

Alzheimer's disease and depression: preclinical comorbidity effects on cognitive functioning.

Both Alzheimer's disease (AD) and depression (D) are prevalent disorders in old age and may co-occur in the same individual. The present study examined whether a diagnosis of D in AD has negative effects on cognitive functioning in the preclinical stage of the diseases, as well as at the time when the diagnoses were rendered. Population-based samples of 13 individuals with incident AD and D, 109 incident AD cases without D, and 179 normal older adults were followed over a three-year period. The groups were compared preclinically and at the time of diagnosis on global cognitive functioning using the MMSE total and the specific item scores, as well as the occurrence of depressive symptoms. As expected, there were clear AD-related deficits preclinically, which were exacerbated at follow-up. In addition, there were D-related deficits on three MMSE items (i.e., following commands, reading, and writing). The poorer performance on the three MMSE items was linked to an elevation of depressive symptoms. However, D was not associated with greater decline in cognitive functioning over the three-year follow-up period. Thus, although depressive symptoms may result in slight cognitive deficits in preclinical AD, at the time of the dementia diagnosis these effects may be absorbed by the neurodegenerative process.

Aged↗
PubMed2005

The age-dependent relation of blood pressure to cognitive function and dementia.

The relation of blood pressure with cognitive function and dementia has, in recent years, received much attention from epidemiological research. Some cross-sectional studies have shown an inverse association between blood pressure and the prevalence of dementia and Alzheimer's disease, whereas longitudinal studies yield mixed results that largely depend on the age at which blood pressure is measured and the time interval between blood pressure and outcome assessments. Some studies suggest that midlife high blood pressure is a risk factor for late-life cognitive impairment and dementia, and that low diastolic pressure and very high systolic pressure in older adults may be associated with subsequent development of dementia and Alzheimer's disease. Observational studies and randomised clinical trials provide limited evidence for a protective effect of antihypertensive therapy against dementia and stroke-related cognitive decline. Atherosclerosis resulting from long-standing hypertension, and cerebral hypoperfusion secondary to severe atherosclerosis and to low blood pressure may be major biological pathways linking both high blood pressure in midlife and low blood pressure in late-life to cognitive decline and dementia.

Aged↗
PubMed2005

Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease.

BACKGROUND: Physical activity may help maintain cognitive function and decrease dementia risk, but epidemiological findings remain controversial. The aim of our study was to investigate the association between leisure-time physical activity at midlife and the subsequent development of dementia and Alzheimer's disease (AD). METHODS: Participants were randomly selected from the survivors of a population-based cohort previously surveyed in 1972, 1977, 1982, or 1987. 1449 persons (72.5%) age 65-79 years participated in the re-examination in 1998 (mean follow-up, 21 years). 117 persons had dementia and 76 had AD. Multiple logistic regression methods were used to analyse the association between leisure-time physical activity and dementia or AD. FINDINGS: Leisure-time physical activity at midlife at least twice a week was associated with a reduced risk of dementia and AD (odds ratio [OR] 0.48 [95% CI 0.25-0.91] and 0.38 [0.17-0.85], respectively), even after adjustments for age, sex, education, follow-up time, locomotor disorders, APOE genotype, vascular disorders, smoking, and alcohol drinking. The associations were more pronounced among the APOE epsilon4 carriers. INTERPRETATION: Leisure-time physical activity at midlife is associated with a decreased risk of dementia and AD later in life. Regular physical activity may reduce the risk or delay the onset of dementia and AD, especially among genetically susceptible individuals.

Aged↗
PubMed2005

Increased cyclin E expression may obviate the role of cyclin D1 during brain development in cyclin D1 knockout mice.

Cyclins D and E play critical roles during the G1 phase of mammalian cell division. Cyclin D1 expression is high and expected to play an important role during mouse brain development. However, in the present study, we found no difference in CNS morphology between cyclin D1 knockout (KO) and control wild-type mice at the ages of 1, 4 and 12 months. Analysis of protein expression in embryonic brains revealed that cyclin E is obviously increased in cyclin D1 KO mice at 13.5 days post coitum. At the same age a high level of cyclin D1 expression is detected in the embryonic brain of wild-type mice. The data indicate that enhanced cyclin E protein expression in cyclin D1 KO mice may obviate the role of cyclin D1 and contribute to the normal brain development of cyclin D1 KO mice.

Animals↗