The Alzheimer variant of Lewy body disease: A pathologically confirmed case-control study

The objective of the study was to identify clinical features that distinguish patients with dementia with Lewy bodies (DLB), who were classified as Alzheimer's disease ( AD) patients, from patients with AD. We examined a group of 27 patients from our memory clinic, originally diagnosed with AD, of whom 6 were postmortem found to have DLB. For the present study, we compared cognitive, noncognitive and neurological symptoms between the two groups. We found that there were no differences on ratings of dementia and scales for activities of daily living. Patients with DLB performed better on the MMSE and the memory subtest of the CAMCOG, but there was no difference in any other cognitive domain. Furthermore, genetic risk factors, including family history of dementia or allele frequency of the apolipoprotein epsilon 4, did not discriminate between the two groups, and there were no differences on CCT scans. Taken together, our findings suggest that Lewy body pathology may be present in patients who do not show the typical clinical features which distinguish DLB from AD. Copyright (C) 2005 S. Karger AG, Basel

Modulation of human endogenous retrovirus (HERV) transcription during persistent and de novo HIV-1 infection

Background: The human genome contains multiple LTR elements including human endogenous retroviruses (HERVs) that together account for approximately 8–9% of the genomic DNA. At least 40 different HERV groups have been assigned to three major HERV classes on the basis of their homologies to exogenous retroviruses. Although most HERVs are silenced by a variety of genetic and epigenetic mechanisms, they may be reactivated by environmental stimuli such as exogenous viruses and thus may contribute to pathogenic conditions. The objective of this study was to perform an in-depth analysis of the influence of HIV-1 infection on HERV activity in different cell types. Results: A retrovirus-specific microarray that covers major HERV groups from all three classes was used to analyze HERV transcription patterns in three persistently HIV-1 infected cell lines of different cellular origins and in their uninfected counterparts. All three persistently infected cell lines showed increased transcription of multiple class I and II HERV groups. Up-regulated transcription of five HERV taxa (HERV-E, HERV-T, HERV-K (HML-10) and two ERV9 subgroups) was confirmed by quantitative reverse transcriptase PCR analysis and could be reversed by knock-down of HIV-1 expression with HIV-1-specific siRNAs. Cells infected de novo by HIV-1 showed stronger transcriptional up-regulation of the HERV-K (HML-2) group than persistently infected cells of the same origin. Analysis of transcripts from individual members of this group revealed up-regulation of predominantly two proviral loci (ERVK-7 and ERVK-15) on chromosomes 1q22 and 7q34 in persistently infected KE37.1 cells, as well as in de novo HIV-1 infected LC5 cells, while only one single HML-2 locus (ERV-K6) on chromosome 7p22.1 was activated in persistently infected LC5 cells. Conclusions: Our results demonstrate that HIV-1 can alter HERV transcription patterns of infected cells and indicate a correlation between activation of HERV elements and the level of HIV-1 production. Moreover, our results suggest that the effects of HIV-1 on HERV activity may be far more extensive and complex than anticipated from initial studies with clinical material

The Rho GDI Rdi1 regulates Rho GTPases by distinct mechanisms

© 2008 by The American Society for Cell Biology. Under the License and Publishing Agreement, authors grant to the general public, effective two months after publication of (i.e.,. the appearance of) the edited manuscript in an online issue of MBoC, the nonexclusive right to copy, distribute, or display the manuscript subject to the terms of the Creative Commons–Noncommercial–Share Alike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0).The small guanosine triphosphate (GTP)-binding proteins of the Rho family are implicated in various cell functions, including establishment and maintenance of cell polarity. Activity of Rho guanosine triphosphatases (GTPases) is not only regulated by guanine nucleotide exchange factors and GTPase-activating proteins but also by guanine nucleotide dissociation inhibitors (GDIs). These proteins have the ability to extract Rho proteins from membranes and keep them in an inactive cytosolic complex. Here, we show that Rdi1, the sole Rho GDI of the yeast Saccharomyces cerevisiae, contributes to pseudohyphal growth and mitotic exit. Rdi1 interacts only with Cdc42, Rho1, and Rho4, and it regulates these Rho GTPases by distinct mechanisms. Binding between Rdi1 and Cdc42 as well as Rho1 is modulated by the Cdc42 effector and p21-activated kinase Cla4. After membrane extraction mediated by Rdi1, Rho4 is degraded by a novel mechanism, which includes the glycogen synthase kinase 3β homologue Ygk3, vacuolar proteases, and the proteasome. Together, these results indicate that Rdi1 uses distinct modes of regulation for different Rho GTPases.Deutsche Forschungsgemeinschaf

Prediction of Dementia in Primary Care Patients

BACKGROUND: Current approaches for AD prediction are based on biomarkers, which are however of restricted availability in primary care. AD prediction tools for primary care are therefore needed. We present a prediction score based on information that can be obtained in the primary care setting. METHODOLOGY/PRINCIPAL FINDINGS: We performed a longitudinal cohort study in 3.055 non-demented individuals above 75 years recruited via primary care chart registries (Study on Aging, Cognition and Dementia, AgeCoDe). After the baseline investigation we performed three follow-up investigations at 18 months intervals with incident dementia as the primary outcome. The best set of predictors was extracted from the baseline variables in one randomly selected half of the sample. This set included age, subjective memory impairment, performance on delayed verbal recall and verbal fluency, on the Mini-Mental-State-Examination, and on an instrumental activities of daily living scale. These variables were aggregated to a prediction score, which achieved a prediction accuracy of 0.84 for AD. The score was applied to the second half of the sample (test cohort). Here, the prediction accuracy was 0.79. With a cut-off of at least 80% sensitivity in the first cohort, 79.6% sensitivity, 66.4% specificity, 14.7% positive predictive value (PPV) and 97.8% negative predictive value of (NPV) for AD were achieved in the test cohort. At a cut-off for a high risk population (5% of individuals with the highest risk score in the first cohort) the PPV for AD was 39.1% (52% for any dementia) in the test cohort. CONCLUSIONS: The prediction score has useful prediction accuracy. It can define individuals (1) sensitively for low cost-low risk interventions, or (2) more specific and with increased PPV for measures of prevention with greater costs or risks. As it is independent of technical aids, it may be used within large scale prevention programs

Structural base for the transfer of GPI-anchored glycoproteins into fungal cell walls

The correct distribution and trafficking of proteins are essential for all organisms. Eukaryotes evolved a sophisticated trafficking system which allows proteins to reach their destination within highly compartmentalized cells. One eukaryotic hallmark is the attachment of a glycosylphosphatidylinositol (GPI) anchor to C-terminal ω-peptides, which are used as a zip code to guide a subset of membrane-anchored proteins through the secretory pathway to the plasma membrane. In fungi, the final destination of many GPIanchored proteins is their outermost compartment, the cell wall. Enzymes of the Dfg5 subfamily catalyze the essential transfer of GPI-anchored substrates from the plasma membrane to the cell wall and discriminate between plasma membrane-resident GPIanchored proteins and those transferred to the cell wall (GPI-CWP). We solved the structure of Dfg5 from a filamentous fungus and used in crystallo glycan fragment screening to reassemble the GPIcore glycan in a U-shaped conformation within its binding pocket. The resulting model of the membrane-bound Dfg5•GPI-CWP complex is validated by molecular dynamics (MD) simulations and in vivo mutants in yeast. The latter show that impaired transfer of GPI-CWPs causes distorted cell-wall integrity as indicated by increased chitin levels. The structure of a Dfg5•β1,3-glycoside complex predicts transfer of GPI-CWP toward the nonreducing ends of acceptor glycans in the cell wall. In addition to our molecular model for Dfg5-mediated transglycosylation, we provide a rationale for how GPI-CWPs are specifically sorted toward the cell wall by using GPI-core glycan modifications

Influence of antipsychotic medication on endogenous retrovirus (ERV) expression in brain cells.

The detection of endogenous retrovirus-derived transcripts in brain samples of patients with schizophrenia and related disorders suggests a possible role of such elements in neuropsychiatric diseases. However, most patients receive antipsychotic drugs that may influence the expression activity of human endogenous retroviruses (HERVs). Monitoring HERV transcription with a retrovirus pol-based DNA chip in a human glioblastoma cell line treated with valproic acid revealed a dose-dependent up-regulation of HERV activity, whereas other antipsychotic drugs such as haloperidol and clozapine showed little or no effect. In brain tissue of rhesus monkeys treated with haloperidol or clozapine no increase of endogenous retrovirus (ERV) transcript levels could be detected

Oncogenic retrovirus from spontaneous murine osteomas : II. Molecular cloning and genomic characterization.

An N-ecotropic murine leukemia virus (OA MuLV), originally isolated from spontaneous osteomas of strain 101 mice, was molecularly cloned. The virus induces osteomas, osteopetrosis, and malignant lymphomas in NMRI mice. The cloned virus was analyzed by heteroduplex analysis, restriction enzyme mapping, and oligonucleotide mapping. The data show a very close relationship to the endogenous Akv prototype virus with some differences in the gag and the env region. The nucleotide sequence of the U3 region of OA MuLV LTR revealed a structure within the presumable enhancer region very similar to the U3 sequences of the FBJ murine sarcoma virus and its associated helper virus. The significance of these specific structures for the oncogenicity of the virus and the development of the typical disease pattern is discussed

Expression and biological significance of human endogenous retroviral sequences.

The human genome contains a variety of elements resembling mammalian retroviruses. Most of these sequences have been found to be related to primate and murine C-type viruses (BaEV, SSAV/GaLV, MuLV), murine B-type viruses and A-type particles (MMTV, IAP), or human T-cell lymphotropic viruses (HTLV). Altogether, human endogenous retroviruses and retroviral elements are estimated to comprise at least 0.1 to 0.6% of the human genome. Like other transposable elements they may contribute in shaping the eukaryotic genome by intracellular transposition events or by generating hot spots of recombination. Human retroviral sequences have been shown to be transcriptionally active, especially in human placenta and embryonic tissue and in human tumor cell lines. Some elements that are coexpressed with cellular sequences are supposed to play a role in regulation of gene expression. Furthermore, expression of human endogenous retroviral sequences may have a protective function against superinfection by related exogenous retroviruses. On the other hand, endogenous retroviruses and retroviral elements represent a cellular reservoir of possibly pathogenic retroviral genes. They may be involved in chromosomal aberrations by acting as sites for recombination events between different chromosomes. Furthermore, they can act as insertion mutagens and activate or inactivate cellular genes. Retroviral gene products themselves may also be pathogenic as has been shown for the immunosuppressive effects of p15E envelope proteins. Therefore, the role of human endogenous retroviruses and retroviral sequences in biological processes is currently a subject of great interest