Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
  • The South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLAM BRC) case register: development and descriptive data.

    29 March 2018

    BACKGROUND: Case registers have been used extensively in mental health research. Recent developments in electronic medical records, and in computer software to search and analyse these in anonymised format, have the potential to revolutionise this research tool. METHODS: We describe the development of the South London and Maudsley NHS Foundation Trust (SLAM) Biomedical Research Centre (BRC) Case Register Interactive Search tool (CRIS) which allows research-accessible datasets to be derived from SLAM, the largest provider of secondary mental healthcare in Europe. All clinical data, including free text, are available for analysis in the form of anonymised datasets. Development involved both the building of the system and setting in place the necessary security (with both functional and procedural elements). RESULTS: Descriptive data are presented for the Register database as of October 2008. The database at that point included 122,440 cases, 35,396 of whom were receiving active case management under the Care Programme Approach. In terms of gender and ethnicity, the database was reasonably representative of the source population. The most common assigned primary diagnoses were within the ICD mood disorders (n = 12,756) category followed by schizophrenia and related disorders (8158), substance misuse (7749), neuroses (7105) and organic disorders (6414). CONCLUSION: The SLAM BRC Case Register represents a 'new generation' of this research design, built on a long-running system of fully electronic clinical records and allowing in-depth secondary analysis of both numerical, string and free text data, whilst preserving anonymity through technical and procedural safeguards.

  • Alzheimer's Disease, Diagnosis and the Need for Biomarkers.

    19 February 2018

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder of aging that presents with memory loss, disorientation, confusion and a reduction in cognitive ability. Although a definite diagnosis of the disorder can only be made post-mortem by histopathological analysis, a number of methods are currently available for the in vivo assessment of AD including psycho-metric tests and neuro-imaging. However, these clinical assessments are relatively nonspecific and imaging is very costly. Genetic testing can be performed if familial AD is suspected, although such cases represent a very small minority of total AD cases. Apolipoprotein E genotype provides a measure for analysing the risk of developing AD, but does not act as an absolute predictive biomarker for AD. Therefore there is a need for an accurate, universal, specific and cost-effective biomarker to facilitate not only ante-mortem diagnosis of AD, but also to allow progression of the disease and response to therapy to be monitored. This is the ultimate goal that our group is pursuing through the pan-European AddNeuroMed project.

  • Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding.

    19 February 2018

    BACKGROUND: Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans-Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as alpha-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1. RESULTS: Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Rossner et al (2004), phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPalpha. CONCLUSION: Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP.

  • Complement factor H Y402H polymorphism is not associated with late-onset Alzheimer's disease.

    28 January 2018

    There is evidence to suggest a role for immune dysfunction in the pathogenesis of Alzheimer's disease, and it has previously been shown that blood plasma levels of the protein complement factor H, a member of the alternative complement pathway, was specifically elevated in people with late-onset Alzheimer's disease. We have genotyped the common complement factor H Y402H polymorphism in a large case-control cohort to investigate association with late-onset Alzheimer's disease susceptibility and find no evidence that this SNP is associated with disease risk. However, it remains possible that another variant in this gene may modify susceptibility for late-onset Alzheimer's disease.

  • Alpha-T-catenin is expressed in human brain and interacts with the Wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer's disease.

    2 April 2018

    The gene encoding alpha-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer's disease (AD), and is therefore a good positional candidate gene for this disorder. We have demonstrated that alpha-T-catenin is expressed in human brain, and like other alpha-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Abeta deposition in brain. To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n > 700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.

  • Identification of genomic organisation, sequence variants and analysis of the role of the human dishevelled 1 gene in late onset Alzheimer's disease.

    1 March 2018

    Alzheimer's disease (AD) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. Neurofibrillary tangles (NFT) are a major pathological hallmark of AD, these are aggregations of paired helical filaments (PHF) comprised of the hyperphosphorylated microtubule associated protein tau. Several kinases, such as glycogen synthase kinase 3 beta (GSK3beta) and c-Jun N-terminal kinase (JNK), phosphorylate tau at sites that are phosphorylated in PHF. Dishevelled 1 (DVL1) is thought to act as a positive regulator of the wnt signalling pathway, and inhibits GSK3beta activity preventing beta-catenin degradation and thus allowing wnt target gene expression. JNK activation is also regulated by DVL1, however it is unclear if this is via the wnt signalling pathway. These observations suggest a central role for DVL1 in tau phosphorylation and AD and led us to investigate DVL1 as a candidate gene for this disorder. We determined the genomic structure of the DVL1 gene by sequencing and data mining and searched for sequence variations in the coding sequences and flanking introns. The DVL1 gene spans a region of approximately 13.8 kb (not including the 5' untranslated region) and is encoded by 15 exons. Analysis of over 4.3 kb of sequence, including 98% of exonic sequences and introns 2, 3, 6, 7, 9, 10, 11 and 12, revealed there to be six rare (< or =6%) sequence variations. None of these had any association with late onset AD. This would suggest that polymorphic variations in the coding sequences of DVL1 are not important in AD. However further analysis of regulatory regions may lead to the identification of other sequence variations which may be implicated in AD.

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

    8 December 2017

    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.

  • Sites of phosphorylation in tau and factors affecting their regulation.

    4 April 2018

    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.

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

    28 January 2018

    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.