Biomedical subjects

S Lovestone

Publications and source records attributed to S Lovestone.

At least 37 records · Page 2Linked to original sources

PubMed2001

Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia.

Cytoarchitectural abnormalities have been reported in the cortex in schizophrenia. These suggest a developmental origin for this disorder. The Wnt signalling pathway is involved in the regulation of brain development; disruption of this pathway may lead to abnormal cortical development. In this study levels of three components of the Wnt signalling pathway; glycogen synthase kinase-3beta(GSK-3beta), beta-catenin and dishevelled-2 (Dvl-2) were determined in the prefrontal cortex of ten schizophrenic and ten control individuals using immunoblotting. GSK-3beta levels were significantly reduced in the schizophrenic group, while levels of beta-catenin and Dvl-2 did not differ between groups. This provides further evidence for an abnormality of the Wnt signalling pathway in schizophrenia.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Effects of FTDP-17 mutations on the in vitro phosphorylation of tau by glycogen synthase kinase 3beta identified by mass spectrometry demonstrate certain mutations exert long-range conformational changes.

In vitro phosphorylation of recombinant wild-type 2N4R tau and FTDP-17 exonic mutant forms P301L, V337M and R406W by glycogen synthase kinase 3beta (GSK3beta) was examined by two dimensional phosphopeptide mapping analysis on thin layer cellulose plates. Comparison of these peptide maps with those generated from wild-type 1N4R tau isoform from which the phosphopeptide constituents and sites of phosphorylation had been determined previously, enabled us to monitor directly changes in phosphorylation of the individual tau proteins. No differences were found in the phosphorylation of wild-type, P301L or V337M tau by GSK3beta but the R406W mutant showed at least two clear differences from the other three tau proteins. The peptides, identified by mass spectrometry corresponding to phosphorylation at both threonine 231 and serine 235 (spot 3), serines 396, 400 and 404 (spot 6a) and serines 195 and 199 (spot 6b) were absent from the R406W peptide map. The findings imply that the R406W mutation in tau exerts long-range conformational effects on the structure of tau.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed2001

The extended haplotype of the microtubule associated protein tau gene is not associated with Pick's disease.

Pick's disease (PiD) is a rare neurodegenerative condition and is a member of a heterogeneous group of disorders known as tauopathies, so-called because of the predominantly neuronal aberrant tau accumulations found in these diseases. The tauopathy, familial frontotemporal dementia (FTD), is caused by mutations in the tau gene. Moreover, progressive supranuclear palsy (PSP) is associated with the tau H1 haplotype. In certain familial forms of FTD and in PSP the microtubule-binding four repeat tau isoform principally accumulates in neuropathological lesions. However, in PiD three repeat tau accumulations are found. We therefore investigated whether either the tau H1 or H2 haplotype was associated with PiD. Our results indicate a slight increase in H2H2 frequency in Pick's cases which is not statistically significant.

Aged↗

PubMed2001

Acetylcholinesterase treatment--modelling potential demand and auditing practice.

BACKGROUND: Acetylcholinesterase inhibitors represent an entirely novel treatment option for patients with Alzheimer's disease (AD). As such they represent a significant change in practice and a significant cost pressure on funding bodies. OBJECTIVES: To assess the impact of cholinesterase inhibitors on routine clinical practice. METHODS: We estimated potential demand for the compounds taking into account eligibility criteria and prescribing practice agreed between clinicians and funders. We then audited actual prescribing practice assessing whether the estimated demand matched actual demand and whether practice and prescribing criteria were adhered to. RESULTS: Over a two-year period we estimated the demand for treatment at a total of 89 patient years for the population of the audit unit. In practice only 24.5 patient years of therapy were received, the short fall apparently being due to low referral rates for treatment. Prescribing by clinicians matched practice guidelines and a high proportion of three monthly assessments using scales for cognition, function and global state were performed. Using these assessment procedures treatment successes could be differentiated from primary and secondary treatment failures and, where apparently appropriate, treatment could be stopped. CONCLUSION: In the real world of clinical practice demand for treatment in AD is modest but likely to grow and assessment with an aim to identifying those receiving benefit from treatment can be achieved.

Aged↗

PubMed2001

Tau proteins with frontotemporal dementia-17 mutations have both altered expression levels and phosphorylation profiles in differentiated neuroblastoma cells.

The inherited form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) has been attributed to mutations in the tau gene. Pathologically, affected FTDP-17 brains share tau aggregates with other tauopathies, the most common being Alzheimer's disease. FTDP-17 mutations may therefore affect tau function leading to tau aggregation and cell loss. Interaction of tau with microtubules is thought to be regulated by phosphorylation. Investigating FTDP-17 mutations transiently expressed as enhanced green fluorescent protein (EGFP)-tagged proteins for the first time in differentiated neuronal cells, we found that two out of three missense mutations showed surprisingly decreased phosphorylation at the pathologically relevant S202/T205 site, mutant EGFP-tau being completely dephosphorylated in most cells. Moreover, phosphorylation at the S396/S404 site was moderately decreased for all mutant isoforms. Although microtubule integrity was not affected, with all mutants tested we demonstrated an increase in cellular tau protein level, some of which is microtubule-bound. Further enhancing this EGFP-tau accumulation by inhibition of tau degradation resulted in the previously less phosphorylated mutant EGFP-tau becoming highly phosphorylated. We conclude that the missense tau mutations primarily result in an excess of neuronal tau, which may interfere with important cellular functions such as axonal transport.

Alzheimer Disease↗

PubMed2001

Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters.

1. Previous data demonstrate that the tricyclic antidepressant, desipramine, induces glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus in L929 cells and increases dexamethasone-induced GR-mediated gene transcription in L929 cells stably transfected with the mouse mammary tumour virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene (LMCAT cells) (Pariante et al., 1997). 2. To extend these findings, the present study has investigated the effects of 24 h coincubation of LMCAT cells with dexamethasone and amitriptyline, clomipramine, paroxetine, citalopram or fluoxetine. 3. All antidepressants, except fluoxetine, enhanced GR-mediated gene transcription, with clomipramine having the greatest effect (10 fold increase). Twenty-four hours coincubation of cells with desipramine, clomipramine or paroxetine, also enhanced GR function in the presence of cortisol, but not of corticosterone. 4. It is proposed that these effects are due to the antidepressants inhibiting the L929 membrane steroid transporter, which actively extrudes dexamethasone and cortisol from the cell, but not corticosterone. This is further confirmed by the fact that clomipramine failed to enhance GR-mediated gene transcription in the presence of dexamethasone when the membrane steroid transporter was blocked by verapamil. 5. The membrane steroid transporters that regulate access of glucocorticoids to the brain in vivo, like the multiple drug resistance p-glycoprotein, could be a fundamental target for antidepressant action.

Animals↗

PubMed2001

Association study of the 5-HT(2A) receptor gene polymorphism, T102C and essential hypertension.

BACKGROUND: Serotonin dysfunction has been implicated in hypertension due to its ability to induce vasoconstriction via stimulation of 5-HT(2) receptors and due to the antihypertensive effect of ketanserin, an antagonist at the 5-HT(2A) receptor subtype, expressed both on arteries and the brain. The silent T102C polymorphism in the 5-HT(2A) gene is in absolute linkage disequilibrium with a polymorphism in the promoter and may contribute to genetic predisposition possibly by modifying the transcription of the gene. OBJECTIVE: To examine the genetic contribution of the T102C 5-HT(2A)polymorphism in essential hypertension in a case-control sample of UK residents. DESIGN: The hypertensive group consisted of 342 subjects over 75 years and the community-based control group consisted of 319 subjects. Subjects were genotyped for the T102C polymorphism by Mspl restriction enzyme digestion following PCR amplification. RESULTS: Sex-specific association analysis revealed significant differences between hypertensive and normotensive subjects in the genotypes distribution (P = 0.016) and allelic frequencies (P = 0.007) in the female group. The direction of significance was increased frequency of the 102-C allele in the hypertensive subjects. There were no association between haplotype and age or body mass index, which suggest that the effect of the T102C variant is not influenced by these variables. CONCLUSION: This data indicates that the T102C polymorphism in the 5-HT(2A) gene might be an independent risk factor for increased blood pressure in female individuals with essential hypertension.

Age Distribution↗

PubMed2001

Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 beta gene and promoter in late onset Alzheimer's disease.

Alzheimer's disease (AD) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. Glycogen synthase kinase 3 beta (GSK3 beta) phosphorylates the microtubule associated protein tau at sites that are aberrantly phosphorylated in AD. GSK3 beta binds to presenilin 1 and plays a role in wnt and insulin signalling cascades, both of which have been proposed to be linked to AD. Moreover GSK3 beta activity may be altered in AD brain. These observations suggest a central role for GSK3 beta in AD and led us to investigate GSK3 beta as a candidate gene for AD. We sought to identify sequence variations in the gene and its promoter, as these could have an effect on activity and expression leading to abnormal function. Sequencing over 3000 bp of the GSK3 beta putative promoter revealed there to be five sequence variations, two of which were common (>10%). However on further examination none of these, either alone or in synergy, had any association with late onset AD. Stratification of the data by APOE epsilon 4 status also produced no significant association. Sequencing of the GSK3 beta coding region revealed no variations. This would suggest that the aberrant phosphorylation of tau by GSK3 beta in AD is not due to sequence variations in the gene or its promoter.

Age of Onset↗

PubMed2001

Sites of phosphorylation in tau and factors affecting their regulation.

The microtubule-associated protein, tau, is the principal component of paired helical filaments (PHFs) in Alzheimer's disease. PHF-tau is highly phosphorylated and a total of 25 sites of phosphorylation have so far been identified. Many of these sites are serine or threonine residues that are immediately followed in the sequence by proline residues, and hence are candidate phosphorylation sites for proline-directed kinases. In vitro, glycogen synthase kinase-3 (GSK-3), extracellular signal-related kinase-1 and -2, and mitogen-activated protein kinases, p38 kinase and c-jun N-terminal kinase, all phosphorylate many of these sites, although with different efficiencies for particular sites. Phosphorylation studies in transfected cells and neurons show that GSK-3 phosphorylates tau more extensively than do these other proline-directed kinases. Mutations in tau have been shown to affect in vitro phosphorylation of tau by GSK-3. The Arg406-->Trp (R406W) tau mutation also affects tau phosphorylation in cells.

Alzheimer Disease↗

PubMed2001

Neurofibrillary tangles and tau phosphorylation.

Neurofibrillary tangles (NFTs) are a characteristic neuropathological lesion of Alzheimer's disease (AD). They are composed of a highly-phosphorylated form of the microtubule-associated protein tau. We are investigating the relationship between NFTs and microtubule stability and how tau phosphorylation and function is affected in transgenic models and by co-expression with beta-amyloid precursor protein and presenilins. In most NFT-bearing neurons, we observed a strong reduction in acetylated alpha-tubulin immunoreactivity (a marker of stable microtubules) and a reduction of the in situ hybridization signal for tubulin mRNA. In transfected cells, mutated tau forms (corresponding to tau mutations identified in familial forms of frontotemporal dementias linked to chromosome 17) were less efficient in their ability to sustain microtubule growth. These observations are consistent with the hypothesis that destabilization of the microtubule network is an important mechanism of cell dysfunction in Alzheimer's disease. The glycogen synthase kinase-3 beta (GSK-3 beta) generates many phosphorylated sites on tau. We performed a neuroanatomical study of GSK-3 beta distribution showing that developmental evolution of GSK-3 beta compartmentalization in neurons paralleled that of phosphorylated tau. Studies on transfected cells and on cultured neurons showed that GSK-3 beta activity controls tau phosphorylation and tau functional interaction with microtubules. Tau phosphorylation was not affected in neurons overexpressing beta-amyloid precursor protein. Transgenic mice expressing a human tau isoform and double transgenic animals for tau and mutated presenilin 1 have been generated; a somatodendritic accumulation of phosphorylated transgenic tau proteins, as observed in the pretangle stage in AD, has been observed but NFTs were not found, suggesting that additional factors might be necessary to induce their formation.

Alzheimer Disease↗

PubMed2001

Apolipoprotein E gene and Alzheimer's disease: is tau the link?

The finding that APOE (the gene encoding apolipoprotein E) polymorphic variation was associated with an altered risk of developing Alzheimer's disease (AD) was a significant advance and immediately prompted a search for the mechanisms responsible for this alteration. Some 6 years later, a number of different hypotheses remain that might account for this influence on pathogenesis with no single mechanism being unequivocally accepted. The different approaches to understanding these mechanisms can be broadly categorized as: those suggesting a remote effect, such as different rates of vascular risk factors in those with the different APOE alleles; those proposing altered neuronal vulnerability, perhaps due to apolipoprotein E (ApoE)-isoform-specific differences in local cholesterol transport; and those hypotheses postulating an ApoE interaction with the two key lesions of AD, plaques and tangles. In this chapter we will review the evidence for and against an interaction between ApoE and the neuronal cytoskeleton, in particular with the microtubule-associated protein tau.

Alleles↗

PubMed2001

Psychosis and aggression in Alzheimer's disease: the effect of dopamine receptor gene variation.

This study investigated possible associations between selected polymorphisms in the dopamine receptor genes DRD1 and DRD3 with the presence of psychotic phenomena or aggressive behaviour in a community based cohort of 134 patients with late onset Alzheimer's disease. An association was found between the presence of psychotic symptoms and aggressive behaviour and the DRD1 polymorphism and between the presence of psychosis, but not aggression, and the DRD3 polymorphism. Specifically, carriers of the DRD1 B2 allele were more likely to be aggressive or experience hallucinations whereas homozygous carriers of the DRD3 1 allele were more likely to experience delusions.

Age of Onset↗

PubMed2001

Genetic risk of Alzheimer's disease: advising relatives.

BACKGROUND: Clinicians are increasingly asked by relatives of patients with Alzheimer's disease to advise on their genetic risk of developing Alzheimer's disease in later life. Many clinicians find this a difficult question to answer. AIMS: To provide information for old age psychiatrists wishing to advise relatives of their risk of developing Alzheimer's disease. METHOD: A selective review of the key literature on the genetic epidemiology of Alzheimer's disease. RESULTS: Currently a DNA diagnosis is attainable in some 70% of families with autosomal dominant Alzheimer's disease. In first-degree relatives of most cases, risk is increased some three- or four-fold relative to controls, but only one-third of this is realised in the average life span. Apolipoprotein E genotyping cannot be used as a predictive test and confers only minimal diagnostic benefit. CONCLUSIONS: Pedigrees with familial Alzheimer's disease should be referred to a Regional Centre for Medical Genetics. Accurate risk prediction is not possible in the vast majority of pedigrees with Alzheimer's disease, although it is possible for the psychiatrist to give a rough estimate of the risk, which can reasonably the couched in reassuring terms.

Aged↗

PubMed2001

Depression, APOE genotype and subjective memory impairment: a cross-sectional study in an African-Caribbean population.

BACKGROUND: Subjective memory impairment (SMI) is common in older populations but its aetiology and clinical significance is uncertain. Depression has been reported to be strongly associated with SMI. Associations with objective cognitive impairment are less clear cut. Other factors suggested to be associated with SMI include poor physical health and the apolipoprotein E (APOE) epsilon4 allele. Studies of SMI have been predominantly confined to white Caucasian populations. METHOD: A community study was carried out in a UK African-Caribbean population aged 55-75, sampled from primary care lists. Twenty-three per cent were classified with SMI. Depression was defined using the 10-item Geriatric Depression Scale. Other aetiological factors investigated were education, objective cognitive function, APOE genotype, disablement and vascular disease/risk. The principal analysis was restricted to 243 participants scoring > 20 on the Mini-Mental State Examination (85%). A second analysis included all 290 participants. RESULTS: Depression, self-reported physical impairment and APOE epsilon4 were associated with SMI. The association between SMI and physical impairment was not explained by depression, vascular disease/risk, or disability/handicap. The association between epsilon4 and SMI increased as MMSE scores decreased and was particularly strong in those with depression. The epsilon4 allele was present in 69% (95% CI 41-89%) of those with depression and SMI compared with 28% (20-36%) of those with neither. CONCLUSIONS: Depression may not be a sufficient explanation for subjective memory complaints. Memory complaints in the presence of depression are associated with high prevalence of epsilon4 and therefore, presumably, a raised risk of subsequent dementia.

Aged↗

PubMed2000

Susceptibility locus for Alzheimer's disease on chromosome 10.

The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.

Age of Onset↗

PubMed2000

Differential effects of apolipoprotein E isoforms on phosphorylation at specific sites on tau by glycogen synthase kinase-3 beta identified by nano-electrospray mass spectrometry.

Previously published data have shown an allele-specific variation in the in vitro binding of apolipoprotein E (apoE) to tau, which prompted the hypothesis that apoE binding may protect tau from phosphorylation, apoE3 being more efficient than apoE4. We have, therefore, investigated the effects of apoE on tau phosphorylation in vitro by the proline-directed kinase, glycogen synthase kinase (GSK)-3 beta. The phosphopeptide maps of tau alone, of tau with apoE3 and of tau with apoE4 were very similar. When apoE2 was present a further four spots were evident. Additionally, of the 15 peptides phosphorylated in the presence or absence of apoE, subtle differences, some isoform-specific, in the relative amounts of phosphorylation were observed.

Apolipoprotein E2↗

PubMed2000

The association between APOE and dementia does not seem to be mediated by vascular factors.

OBJECTIVE: The effect of APOE on dementia may be mediated through dyslipidemia and atherogenesis through its effect on cholesterol metabolism. The authors investigated this possibility among aged survivors from the UK Medical Research Council Trial of the Treatment of Hypertension in Older Adults. DESIGN: A total of 370 of 657 survivors from an initial cohort of 1,088 recruited into the trial between 1983 and 1985 were traced in 1994 and agreed to be screened for dementia. Blood samples were analyzed for APOE genotype and serum fibrinogen. Cholesterol level, smoking behavior, blood pressure, body mass index, and EKG recordings had been measured at recruitment 10 to 12 years earlier. Odds ratios (ORs) for the association between APOE epsilon4/* and both AD and dementia were estimated and adjusted incrementally for the effect of age and premorbid intelligence, cholesterol, other risk factors for vascular disease, and EKG evidence of cardiovascular disease. RESULTS: The authors diagnosed 24 cases of National Institute of Neurological and Communicative Disorders and Stroke AD from 41 cases of dementia. The crude OR for the association between APOE epsilon4/* and AD was 3.40 (95% CI 1.30 to 8.91). APOE genotype was associated with serum cholesterol level, and there was a nonsignificant trend for an association with smoking behavior. After adjusting for these and all other vascular risk factors and vascular disease variables listed earlier, the OR for the association between APOE epsilon4/* and AD increased to 4.81 (1.60 to 14.4). CONCLUSION: Presence of APOE epsilon4/* seems to increase the risk for dementia and AD independently of its effect on dyslipidemia and atherogenesis.

Aged↗

PubMed2000

The function of the microtubule-associated protein tau is variably modulated by graded changes in glycogen synthase kinase-3beta activity.

The microtubule-associated protein tau favors microtubule nucleation and stabilization and plays a role in the elongation of axons. We have investigated the ability of glycogen synthase kinase-3beta (GSK-3beta) to control tau-induced processes outgrowth. Tau-transfected Chinese hamster ovary (CHO) cells developed processes containing microtubule bundles after cytochalasin treatment, but a significant reduction in the number of cells harboring processes was observed in tau/GSK-3beta-co-transfected cells. Lithium, an inhibitor of GSK-3beta, counteracted in a dose-dependent manner this inhibitory effect of GSK-3beta. These findings suggest that GSK-3beta modulates in a graded manner the ability of tau to control the microtubule-dependent induction of cell processes.

Animals↗