Biomedical subjects

Bengt Winblad

Publications and source records attributed to Bengt Winblad.

At least 73 records · Page 4Linked to original sources

PubMed2005

Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3beta in SH-SY5Y neuroblastoma cells.

We have previously reported an aberrant accumulation of activated protein kinase B (PKB), glycogen synthase kinase (GSK)-3beta, extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38 and p70 S6 kinase (p70S6K) in neurons bearing neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). However, the mechanism by which these tau candidate kinases are involved in the regulation of p70S6K and GSK-3beta phosphorylation is unknown. In the current study, 100 microM zinc sulfate was used, and influences of various components of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on p70S6K and GSK-3beta phosphorylation have been investigated in serum-deprived SH-SY5Y neuroblastoma cells. We found that zinc could induce an increase of phosphorylated (p) p70S6K, p-PKB, p-GSK-3beta, p-ERK1/2, p-JNK and p-p38, especially in long-term treatment (4-8 h). Treatment with different inhibitors including rapamycin, wortmannin, LY294002, and U0126, and their combinations, indicated that phosphorylation of p70S6K and GSK-3beta is regulated by rapamycin-dependent, PI3K and MAPK pathways. Furthermore, phosphorylation of p70S6K and GSK-3beta affected levels of tau unphosphorylated at the Tau-1 site and phosphorylated at the PHF-1 site, and p70S6K phosphorylation affected the total tau level. Thus, 100 microM zinc might activate PKB, GSK-3beta, ERK1/2, JNK, p38 and p70S6K, that are consequently involved in tau changes in SH-SY5Y cells.

Analysis of Variance↗

PubMed2005

Piracetam: a review of pharmacological properties and clinical uses.

Piracetam, a derivative of the neurotransmitter gamma-aminobutyric acid (GABA), has a variety of physiological effects that may result, at least in part, from the restoration of cell membrane fluidity. At a neuronal level, piracetam modulates neurotransmission in a range of transmitter systems (including cholinergic and glutamatergic), has neuroprotective and anticonvulsant properties, and improves neuroplasticity. At a vascular level, it appears to reduce erythrocyte adhesion to vascular endothelium, hinder vasospasm, and facilitate microcirculation. This diverse range of physiological effects is consistent with its use in a range of clinical indications. Its efficacy is documented in cognitive disorders and dementia, vertigo, cortical myoclonus, dyslexia, and sickle cell anemia. While high doses are sometimes necessary, piracetam is well tolerated.

Anemia, Sickle Cell↗

PubMed2005

Dental caries, periodontal disease, and cardiac arrhythmias in community-dwelling older persons aged 80 and older: is there a link?

OBJECTIVES: To examine whether caries or periodontitis is associated with cardiac arrhythmias in community-dwelling people aged 80 and older. SETTING: Urban, community-based population in Stockholm, Sweden. DESIGN: Cross-sectional. PARTICIPANTS: Eligible persons were identified through the Kungsholmen Project, which is an ongoing, longitudinal, population-based study of the oldest old. The present study included 125 dentate individuals. MEASUREMENTS: Data from interviews, a medical examination, and an oral examination. The assessment of cardiac arrhythmia was based on a clinical examination by a physician or the Stockholm Inpatient Register. Active root caries, active coronal caries, and periodontitis were assessed using previously defined National Institute of Dental and Craniofacial Research diagnostic criteria. RESULTS: The primary finding of the multivariate logistic regression analysis was that persons with three or more active root caries lesions had more than twice the odds of cardiac arrhythmias than persons without active root caries. The results did not notably change after adjusting for age, medications that reduce saliva, and number of teeth. Persons with one to two active coronal caries lesions had 2.8 times higher odds (95% confidence interval=1.1-7.0) of arrhythmia than persons without active coronal caries, but there was no greater risk for persons with three or more coronal caries lesions. There was no association between periodontal disease and arrhythmia. CONCLUSION: The findings indicate that there may be a link between active root caries and cardiac arrhythmias in the oldest old. Nevertheless, although a biological pathway is not obvious, it is plausible that both are simply markers of declining general health. The results suggest the need for further study of these relationships.

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PubMed2005

Collagenous Alzheimer amyloid plaque component assembles amyloid fibrils into protease resistant aggregates.

Recently, a novel plaque-associated protein, collagenous Alzheimer amyloid plaque component (CLAC), was identified in brains from patients with Alzheimer's disease. CLAC is derived from a type II transmembrane collagen precursor protein, termed CLAC-P (collagen XXV). The biological function and the contribution of CLAC to the pathogenesis of Alzheimer's disease and plaque formation are unknown. In vitro studies indicate that CLAC binds to fibrillar, but not to monomeric, amyloid beta-peptide (Abeta). Here, we examined the effects of CLAC on Abeta fibrils using assays based on turbidity, thioflavin T binding, sedimentation analysis, and electron microscopy. The incubation of CLAC with preformed Abeta fibrils led to increased turbidity, indicating that larger aggregates were formed. In support of this contention, more Abeta was sedimented in the presence of CLAC, as determined by gel electrophoresis. Moreover, electron microscopy revealed an increased amount of Abeta fibril bundles in samples incubated with CLAC. Importantly, the frequently used thioflavin T-binding assay failed to reveal these effects of CLAC. Digestion with proteinase K or trypsin showed that Abeta fibrils, incubated together with CLAC, were more resistant to proteolytic degradation. Therefore, CLAC assembles Abeta fibrils into fibril bundles that have an increased resistance to proteases. We suggest that CLAC may act in a similar way in vivo.

Alzheimer Disease↗

PubMed2005

Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain.

The pathogenesis of formation of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains is unknown. One of the possibilities might be that translation of tau mRNA is aberrantly regulated in AD brains. In the current study, levels of various translation control elements including total and phosphorylated (p) forms of mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), eukaryotic elongation factor 2 (eEF2), and eEF2 kinase were investigated in relationship with tau in homogenates of the medial temporal cortex from 20 AD and 10 control brains. We found that levels of p-mTOR (Ser2481), and p-4E-BP1 (Thr70 and Ser65) dramatically increase in AD, and are positively significantly correlated with total tau and p-tau. Levels of p-eEF2K were significantly increased, and total eEF2 significantly decreased in AD, when compared to controls. The changes of p-mTOR (2481), p-4E-BP1, and p-eEF2 were immunohistochemically confirmed to be in neurons of AD brains. This suggested that there are obvious abnormalities of elements related with translation control in AD brain and their aberrant changes may up-regulate the translation of tau mRNA, contributing to hyperphosphorylated tau accumulation in NFT-bearing neurons.

Adaptor Proteins, Signal Transducing↗

PubMed2005

The strength of two indicators of social position on oral health among persons over the age of 80 years.

OBJECTIVE: The objective of the present study is to analyze how two dimensions of social position, education and social class, are associated with oral health among generally healthy, community-dwelling persons over the age of 80 years. METHODS: The present investigation is based on a sample of 157 community-dwelling individuals from The Kungsholmen Elders Oral Health Study (KEOHS) and included data from interviews and oral examinations. Social position was measured by education and social class. Oral health was measured by active coronal caries, active root caries, edentulism and use of dental services. RESULTS: The primary findings of the adjusted multivariate logistic regression analysis were that, compared to persons who had been in higher positions, persons who had been blue-collar/ white-collar workers had significantly greater odds of having coronal caries and high, but nonsignificant odds of being edentulous. Further, persons with elementary/ medium education tended to forego regular dental services more than persons with high education. CONCLUSION: The study identified social inequalities in oral health even in a population of independently living, generally healthy very old Swedes and in a country where the public health policies have tried to minimize these inequalities.

Age Factors↗

PubMed2005

[Risk factors for dementia and Alzheimer' s disease-findings from a community-based cohort study in Stockholm, Sweden].

OBJECTIVE: It is known that dementia is a multi-factorial disorder, but the etiological factors other than aging remain to be explored, hence we sought to investigate the risk factors of dementia and Alzheimer's disease (AD). METHODS: We followed a community-based dementia-free cohort (n = 1301) aged 75 years and over in Stockholm, Sweden. Baseline data were obtained through a structured interview and extensive clinical examination, or by reviewing the inpatient register database. We used the DSM-III-R criteria to define dementia and AD cases. RESULTS: Over six years of a follow-up program,350 subjects were diagnosed as dementia, including 260 Alzheimer cases. Multiple Cox regression analysis suggested that older age,low education (< 8 years), cognitive impairment, functional disability (ADL > or = 1), low diastolic pressure (< 70 mm Hg), diabetes mellitus, coronary heart disease, and APOEepsilon4 allele were significantly or marginally associated with subsequent development of dementia and AD. Dementia was related also to stroke and atrial fibrillation. Antihypertensive drug use was associated with a lower risk of AD and dementia. CONCLUSIONS: Our study revealed that some sociodemographic features, cognitive and physical dysfunctions, vascular disorders, and genetic susceptibility were major risk factors for dementia and AD. Use of antihypertensive drugs might protect against the dementing disorders in a very old population.

Aged↗

PubMed2004

Characterization of the Alzheimer's disease-associated CLAC protein and identification of an amyloid beta-peptide-binding site.

Amyloid beta-peptide (Abeta) deposition into amyloid plaques is one of the invariant neuropathological features of Alzheimer's disease. Other proteins co-deposit with Abeta in plaques, and one recently identified amyloid-associated protein is the collagen-like Alzheimer amyloid plaque component CLAC. It is not known how CLAC deposition affects Abeta plaque genesis and the progress of the disease. Here, we studied the in vitro properties of CLAC purified from a mammalian expression system. CLAC displays features characteristic of a collagen protein, e.g. it forms a partly protease-resistant triple-helical structure, exhibits an intermediate affinity for heparin, and is glycosylated. Purified CLAC was also used to investigate the interaction between CLAC and Abeta. Using a solid-phase binding assay, we show that CLAC bound with a similar affinity to aggregates formed by Abeta-(1-40) and Abeta-(1-42) and that the interaction was impaired by increasing salt concentrations. An 8-residue-long sequence located in non-collagenous domain 2 of CLAC was found to be crucial for the interaction with Abeta. These findings may be useful for future therapeutic interventions aimed at finding compounds that modulate the binding of CLAC to Abeta deposits.

Alzheimer Disease↗

PubMed2004

Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain.

Eukaryotic translation factor 4E (eIF4E) plays a key role in regulating protein translation. It was thought that in order to maintain neuronal functions, tau protein is continuously generated to compensate those being hyperphosphorylated and compromised in its ability to promote and maintain microtubule assembly in Alzheimer's disease. If eIF4E is involved in tau mRNA translation, level of eIF4E phosphorylation should be changed. In the current study, we found a dramatic increase of phosphorylated eIF4E in Alzheimer's disease, especially in those cases with late stages of neurofibrillary changes. Level of eIF4E phosphorylation is significantly correlated with total- and Alzheimer hyperphosphorylated taus. These data suggest that the increase of eIF4E phosphorylation is involved in formation of Alzheimer neurofibrillary changes.

Aged↗

PubMed2004

Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria.

Mitochondria are central in the regulation of cell death. Apart from providing the cell with ATP, mitochondria also harbor several death factors that are released upon apoptotic stimuli. Alterations in mitochondrial functions, increased oxidative stress, and neurons dying by apoptosis have been detected in Alzheimer's disease patients. These findings suggest that mitochondria may trigger the abnormal onset of neuronal cell death in Alzheimer's disease. We previously reported that presenilin 1 (PS1), which is often mutated in familial forms of Alzheimer's disease, is located in mitochondria and hypothesized that presenilin mutations may sensitize cells to apoptotic stimuli at the mitochondrial level. Presenilin forms an active gamma-secretase complex together with Nicastrin (NCT), APH-1, and PEN-2, which among other substrates cleaves the beta-amyloid precursor protein (beta-APP) generating the amyloid beta-peptide and the beta-APP intracellular domain. Here we have identified dual targeting sequences (for endoplasmic reticulum and mitochondria) in NCT and showed expression of NCT in mitochondria by immunoelectron microscopy. We also showed that NCT together with APH-1, PEN-2, and PS1 form a high molecular weight complex located in mitochondria. gamma-secretase activity in isolated mitochondria was demonstrated using C83 (alpha-secretase-cleaved C-terminal 83-residue beta-APP fragment from BD8 cells lacking presenilin and thus gamma-secretase activity) or recombinant C100-Flag (C-terminal 100-residue beta-APP fragment) as substrates. Both systems generated an APP intracellular domain, and the activity was inhibited by the gamma-secretase inhibitors l-685,458 or Compound E. This novel localization of NCT, PS1, APH-1, and PEN-2 expands the role and importance of gamma-secretase activity to mitochondria.

Adenosine Triphosphate↗

PubMed2004

The extreme C terminus of presenilin 1 is essential for gamma-secretase complex assembly and activity.

The gamma-secretase complex catalyzes the cleavage of the amyloid precursor protein in its transmembrane domain resulting in the formation of the amyloid beta-peptide and the cytoplasmic APP intracellular domain. The active gamma-secretase complex is composed of at least four subunits: presenilin (PS), nicastrin, Aph-1, and Pen-2, where the presence of all components is critically required for gamma-cleavage to occur. The PS proteins are themselves subjected to endoproteolytic cleavage resulting in the generation of an N-terminal and a C-terminal fragment that remain stably associated as a heterodimer. Here we investigated the effects of modifications on the C terminus of PS1 on PS1 endoproteolysis, gamma-secretase complex assembly, and activity in cells devoid of endogenous PS. We report that certain mutations and, in particular, deletions of the PS1 C terminus decrease gamma-secretase activity, PS1 endoproteolysis, and gamma-secretase complex formation. We demonstrate that the N- and C-terminal PS1 fragments can associate with each other in mutants having C-terminal truncations that cause loss of interaction with nicastrin and Aph-1. In addition, we show that the C-terminal fragment of PS1 alone can mediate interaction with nicastrin and Aph-1 in PS null cells expressing only the C-terminal fragment of PS1. Taken together, these data suggest that the PS1 N- and C-terminal fragment intermolecular interactions are independent of an association with nicastrin and Aph-1, and that nicastrin and Aph-1 interact with the C-terminal part of PS1 in the absence of an association with full-length PS1 or the N-terminal fragment.

Amyloid Precursor Protein Secretases↗

PubMed2004

Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study.

OBJECTIVE: To evaluate the relation between midlife alcohol consumption and mild cognitive impairment and dementia in old age, and the possible modification of this relation by apolipoprotein E. DESIGN: Prospective, population based study. SETTING: Populations of Kuopio and Joensuu, eastern Finland. PARTICIPANTS: Of 1464 men and women aged 65-79 years randomly selected from population based samples studied in 1972 or 1977, 1018 (70%) were re-examined in 1998 (after an average follow up of 23 years). MAIN OUTCOME MEASURES: Mild cognitive impairment and dementia in old age. RESULTS: Participants who drank no alcohol at midlife and those who drank alcohol frequently were both twice as likely to have mild cognitive impairment in old age as those participants who drank alcohol infrequently. The risk of dementia related to alcohol drinking was modified by the presence of the apolipoprotein e4 allele. The carriers of apolipoprotein e4 had an increased risk of dementia with increasing alcohol consumption: compared with non-carriers who never drank, the odds ratio for carriers who never drank was 0.6, for infrequent drinkers it was 2.3, and for frequent drinkers was 3.6 (the overall interaction term "drinking frequency(*)apolipoprotein e4" was significant (P = 0.04), as were the interactions "infrequent drinking(*)apolipoprotein e4" (P = 0.02) and "frequent drinking(*)apolipoprotein e4" (P = 0.03)). Non-carriers of apolipoprotein e4 had similar odds ratios for dementia irrespective of alcohol consumption. CONCLUSION: Alcohol drinking in middle age showed a U shaped relation with risk of mild cognitive impairment in old age. Risk of dementia increased with increasing alcohol consumption only in those individuals carrying the apolipoprotein e4 allele.

Aged↗

PubMed2004

Decline in blood pressure over time and risk of dementia: a longitudinal study from the Kungsholmen project.

BACKGROUND AND PURPOSE: Low blood pressure has been related to an increased risk of dementia. We sought to verify blood pressure variations before and after a dementia diagnosis and to relate blood pressure decline to subsequent Alzheimer disease and dementia. METHODS: A community dementia-free cohort aged > or =75 years (n=947) underwent follow-up examinations twice over a period of 6 years to detect dementia cases (Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised [DSM-III-R] criteria, n=304). Blood pressure variation before and after dementia diagnosis was verified with linear mixed-effects models. Using the dementia-free cohort identified at first follow-up (n=719), the association between blood pressure decline from baseline to first follow-up and subsequent risk of dementia was examined. RESULTS: Blood pressure markedly decreased over 3 years before dementia diagnosis and afterward, whereas no substantial decline was present 3 to 6 years before the diagnosis. However, among subjects with baseline systolic pressure <160 mm Hg, systolic pressure decline > or =15 mm Hg occurring 3 to 6 years before diagnosis was associated with relative risks (95% CI) of 3.1 (1.3 to 7.0) for Alzheimer disease and 3.1 (1.5 to 6.3) for dementia. There was a dose-response relationship between systolic pressure decline and dementia risk in subjects with vascular disease. CONCLUSIONS: Blood pressure starts to decrease only 3 years before dementia diagnosis and continues to decline afterward. A greater decline in systolic pressure occurring 3 to 6 years before diagnosis is associated with an increased risk of dementia only in older people with already low blood pressure or affected by vascular disorders.

Aged↗

PubMed2004

Effects of chronic overexpression of interleukin-1 receptor antagonist in a model of permanent focal cerebral ischemia in mouse.

Interleukin-1 receptor antagonist (IL-1ra) has been shown previously to have neuroprotective effects in animal models of stroke. The effects of chronic overexpression of human soluble IL-1ra (hsIL-1ra) were studied in a mouse model of permanent focal cerebral ischemia. A transgenic mouse strain (Tg hsIL-1ra+/-) has been developed using the promoter for glial fibrillary acidic protein (GFAP) to limit the overexpression to the CNS. Analysis of the neurological scores, infarct volume and edema formation revealed no differences between Tg hsIL-1ra+/- and wild-type (WT) mice. The cerebral ischemia resulted in pronounced astrocyte proliferation and microglial activation, as well as induction of inflammatory markers in both Tg hsIL-1ra+/- and WT mice, with no major differences between the two genotypes. Interestingly, hsIL-1ra expression in astrocytes was reduced in infarcted areas as compared to non-ischemic regions and sham-operated controls. In conclusion, transgenic overexpression of hsIL1-ra was not neuroprotective in this cerebral ischemia model, possibly due to insufficient levels for protection against the extensive lesion, or an up-regulation of compensatory inflammatory signals due to the lifetime blockade of IL-1 receptors.

Animals↗

PubMed2004

Akt activity in Alzheimer's disease and other neurodegenerative disorders.

Enzyme activities of the serine/threonine kinase Akt were compared in mid-temporal and mid-frontal cortices from Alzheimer's disease cases and matched controls. Activities (GSK-3alpha/beta fusion protein phosphorylation by immunoprecipitated Akt) were significantly increased in temporal cortex soluble fractions from Alzheimer's disease compared with non-disease controls and positive disease controls with another neurodegenerative disease. Temporal cortex soluble fraction Akt activities positively correlated with Braak staging for neurofibrillary changes. Frontal cortex soluble fraction activities were significantly reduced in positive disease compared with Alzheimer's disease cases and non-disease controls. Strong Ser Akt immunoreactivity was seen in Alzheimer's disease pyramidal neurons likely undergoing degeneration and in reactive astroglia. Non-disease and positive disease controls showed moderate Ser Akt immunostaining of occasional pyramidal neurons.

Aged↗

PubMed2004

Patients with Alzheimer's disease may be particularly susceptible to adverse effects of statins.

In epidemiological, cross-sectional studies, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) prevented to a large extent the development of Alzheimer's disease (AD), but the results of randomized, placebo-controlled studies, focused on statin therapy in patients with ischemic heart disease (IHD), are at variance. Nonetheless, data from epidemiological, longitudinal studies in humans as well as studies on transgenic mouse models and cultured neuronal cell lines indicate that cholesterol may contribute to the pathogenesis of AD. Statins have proven therapeutic and preventive effects in IHD and other vascular diseases in man. They generally are well tolerated, but some adverse effects, probably due to antiproliferative and proapoptotic properties of the statins, are matters of concern. AD patients may be extrasusceptible to adverse effects of statins due to preexisting aberrations in signal transduction and energy metabolism in the neurons and a perturbed cholesterol metabolism in the brain. This problem might be addressed in randomized, double-blind studies with statins in AD. The statins differ from each other in several aspects, and they are not considered to be therapeutically interchangeable. It could be fruitful to use both a placebo and two different types of statins, i.e. an essentially hydrophilic statin and a lipophilic statin, in a double-blinded fashion, and to compare the effects on the cognitive decline in AD.

Aged↗

PubMed2004

Relation of education and occupation-based socioeconomic status to incident Alzheimer's disease.

In this study, the authors evaluated whether the association between low educational level and increased risk of Alzheimer's disease (AD) and dementia may be explained by occupation-based socioeconomic status (SES). A cohort of 931 nondemented subjects aged > or = 75 years from the Kungsholmen Project, Stockholm, Sweden, was followed for 3 years between 1987 and 1993. A total of 101 incident cases of dementia, 76 involving AD, were detected. Less-educated subjects had an adjusted relative risk of developing AD of 3.4 (95% confidence interval: 2.0, 6.0), and subjects with lower SES had an adjusted relative risk of 1.6 (95% confidence interval: 1.0, 2.5). When both education and SES were introduced into the same model, only education remained significantly associated with AD. Combinations of low education with low or high SES were associated with similar increased risks of AD, but well-educated subjects with low SES were not at high risk. Low SES at 20 years of age, even when SES was high at age 40 or 60 years, was associated with increased risk; however, this increase disappeared when education was entered into the model. In conclusion, the association between low education and increased AD risk was not mediated by adult SES or socioeconomic mobility. This suggests that early life factors may be relevant.

Aged↗

PubMed2004

APOE genotype, family history of dementia, and Alzheimer disease risk: a 6-year follow-up study.

BACKGROUND: Both family aggregation and apolipoprotein E (APOE) epsilon4 allele are well-known risk factors for dementia, but the relation between these two factors remains unclear. OBJECTIVE: To explore whether the risk of dementia and Alzheimer disease (AD) due to a positive family history is explained by APOE genotypes. DESIGN: Community-based cohort study. SETTING: The Kungsholmen district of Stockholm, Sweden. PARTICIPANTS: A total of 907 nondemented people 75 years or older, followed up for 6 years to detect incident dementia and AD cases according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. MAIN OUTCOME MEASURES: Risk of dementia and AD by Cox proportional hazards models after controlling for several potential confounders. RESULTS: Subjects who had at least 2 siblings with dementia were at an increased risk of AD. Individuals with both APOE epsilon4 allele and at least 2 affected first-degree relatives had a higher risk of dementia and AD compared with those without these 2 factors. Similar results were obtained for history of dementia separately in parents or siblings. Among the epsilon4 allele carriers, subjects with 2 or more first-degree demented relatives had increased risk of dementia and AD, whereas no increased risk was detected among non-epsilon4 carriers. CONCLUSIONS: Family history of dementia was associated with an increased risk of dementia and AD in this very old population, but only among APOE epsilon4 carriers. This suggests the existence of other genetic or environmental risk factors that may be active in the presence of the APOE epsilon4 allele.

Aged↗