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Biomedical subjects

W Scheper

Publications and source records attributed to W Scheper.

16 recordsLinked to original sources
PubMed2006

The significance of neuroinflammation in understanding Alzheimer's disease.

The interest of scientists in the involvement of inflammation-related mechanisms in the pathogenesis of Alzheimer's disease (AD) goes back to the work of one of the pioneers of the study of this disease. About hundred years ago Oskar Fischer stated that the crucial step in the plaque formation is the extracellular deposition of a foreign substance that provokes an inflammatory reaction followed by a regenerative response of the surrounding nerve fibers. Eighty years later immunohistochemical studies revealed that amyloid plaques are indeed co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. These findings have led to the view that the amyloid plaque is the nidus of a non-immune mediated chronic inflammatory response locally induced by fibrillar A beta deposits. Recent neuropathological studies show a close relationship between fibrillar A beta deposits, inflammation and neuroregeneration in relatively early stages of AD pathology preceding late AD stages characterized by extensive tau-related neurofibrillary changes. In the present work we will review the role of inflammation in the early stage of AD pathology and particularly the role of inflammation in A beta metabolism and deposition. We also discuss the possibilities of inflammation-based therapeutic strategies in AD.

Alzheimer Disease↗
PubMed2006

Always around, never the same: pathways of amyloid beta induced neurodegeneration throughout the pathogenic cascade of Alzheimer's disease.

There is an increasing amount of evidence showing the importance of intermediate aggregation species of amyloid beta (Abeta) in the pathogenic cascade of Alzheimer's disease (AD). Different Abeta assembly forms may mediate diverse toxic effects at different stages of the disease. Mouse models for AD suggest that intraneuronal accumulation of Abeta oligomers might be involved in AD pathogenesis at a very early stage of the disease. The detrimental effect of oligomeric Abeta on synaptic efficacy is suggested to be an early event in the pathogenic cascade. Also early neuronal responses as activation of the unfolded protein response are processes likely to be associated with the increased occurrence of oligomeric or low fibrillar Abeta in AD pathology. In later stages of AD pathology, the fibrillarity of Abeta increases, concomitantly with a neuroinflammatory response, followed by tau related neurofibrillary changes in end stage pathology. We will review recent findings in in vitro cell models, in vivo mouse models, and post mortem AD brain tissue in view of the effects of different Abeta peptide species on neurodegeneration during AD pathogenesis. Insight into the role of different Abeta species during AD pathogenesis is essential for the development of disease modifying drugs and therapeutical strategies.

Alzheimer Disease↗
PubMed2005

The unfolded protein response is activated in Alzheimer's disease.

Alzheimer's disease (AD) is, at the neuropathological level, characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR) that may protect the cell against the toxic buildup of misfolded proteins. In this study we investigated the activation of the UPR in AD. Protein levels of BiP/GRP78, a molecular chaperone which is up-regulated during the UPR, was found to be increased in AD temporal cortex and hippocampus as determined by Western blot analysis. At the immunohistochemical level intensified staining of BiP/GRP78 was observed in AD, which did not co-localize with AT8-positive neurofibrillary tangles. In addition, we performed immunohistochemistry for phosphorylated (activated) pancreatic ER kinase (p-PERK), an ER kinase which is activated during the UPR. p-PERK was observed in neurons in AD patients, but not in non-demented control cases and did not co-localize with AT8-positive tangles. Overall, these data show that the UPR is activated in AD, and the increased occurrence of BiP/GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the UPR early in AD neurodegeneration. Although the initial participation of the UPR in AD pathogenesis might be neuroprotective, sustained activation of the UPR in AD might initiate or mediate neurodegeneration.

Adult↗
PubMed2005

Protein quality control in Alzheimer's disease: a fatal saviour.

Aggregation of Abeta plays a key role in the pathogenesis of Alzheimer's disease. Although the highly structured Abeta aggregates (fibrils) have long been thought to be the toxic form of Abeta, recent evidence suggests that smaller, soluble intermediates in Abeta aggregation are the real culprit. Because these oligomeric aggregates are already formed in the secretory pathway, this raises another issue: Is intra- or extracellular Abeta involved in the pathogenic cascade? Because aggregated proteins are very toxic, cells have developed quality control responses to deal with such proteins. A prime site for quality culum. Here, aberrant proteins are recognized and can be targeted for degradation to the cytosolic quality control system. In addition, there is accumulating evidence for quality control in other subcellular compartments in the cell. All quality control mechanisms are initially protective, but will become destructive after prolonged accumulation of aggregated proteins. This is enhanced by decreased efficiency of these systems during aging and therefore, these responses may play an important role in the pathogenesis of Alzheimer's disease. In this review, we will discuss the role of protein quality control in the neurotoxicity of Abeta.

Alzheimer Disease↗
PubMed2000

Alzheimer's presenilin 1 is a putative membrane receptor for rab GDP dissociation inhibitor.

Mutations in the presenilin 1 ( PS-1 ) gene cause Alzheimer's disease (AD). These mutations alter the processing of the amyloid precursor protein (APP) by increasing the production of the fibrillogenic amyloid fragment, Abeta1-42/43. Since the secretase activities that process APP are localized in different intracellular compartments, it is likely that membrane transport is a key factor in the pathogenesis of AD. In this report we provide evidence for a direct connection between PS-1 and membrane transport. We show that the N-terminus of PS-1 binds to rab GDP dissociation inhibitor (rabGDI), a regulatory factor in vesicle transport. In PS-1-deficient neurons we found a 2-fold decrease in the amount of rabGDI associated with membranes. Our findings are compatible with PS-1 being a membrane receptor for rabGDI. This is in line with a role of PS-1 in the regulation of protein trafficking in the ER/Golgi, which can modulate the production of Abeta.

Adult↗
PubMed1998

[Proteins with frameshift mutations in Alzheimer's disease; cause or effect?].

In a recent paper in Science, a novel finding was presented on Alzheimer's disease. The authors describe mutant proteins, brought about by a change in the mRNA reading frame. These so-called +I proteins appear to be associated with neuropathological changes in Alzheimer's disease brains. Two proteins involved in the pathogenesis of the disease were studied: beta-amyloid precursor protein en ubiquitin-B. For both proteins, a deletion of two bases in a small percentage of the mRNAs caused the frame shift. Possible mechanisms and implications are discussed.

Alzheimer Disease↗
PubMed1998

[Presenilins as a marker of Alzheimer's disease].

Although the sporadic form of Alzheimer's disease is the most common, rare familial variants exist. Approximately 50% of these cases are caused by a mutation in the presenilin genes. Mutations in presinilin genes give rise to Alzheimer's disease in a dominant pattern of inheritance with an early age of onset (< 60 years). Both presenilins (PS-1 and PS-2) are transmembrane proteins localized in the intracellular membranes of the endoplasmatic reticulum and Golgi apparatus. This suggests they play a role in transport or sorting of proteins in the cell. Different lines of evidence directly link presenilin to the formation of beta-amyloid, an important constituent of senile plaques. PS-1 has an essential function during development: mice lacking intact PS-1 are not viable. In addition, structural and functional homologies have been identified between presenilins and Notch signal transduction pathways, which play a role in development. The discovery of the presenilin mutations has provided a new angle to Alzheimer's disease research. Eventually, this will probably greatly contribute to knowledge of the pathogenesis of the disease and in time support the development of novel therapeutic strategies.

Alzheimer Disease↗
PubMed1996

Growth-condition-dependent regulation of insulin-like growth factor II mRNA stability.

Insulin-like growth factor II (IGF-II) is synthesized in many tissues, but the main site of production is the liver. In this paper we show that IGF-II mRNA levels are dependent on the growth conditions of the cells. In Hep3B cells, serum deprivation leads to a marked increase in IGF-II mRNA levels. Serum stimulation of starved Hep3B cells induces a decrease in the amount of IGF-II mRNA, which is not caused by a change in promoter activity. IGF-II mRNAs are subject to endonucleolytic cleavage, a process that requires two widely separated elements in the 3' untranslated region of the mRNA. Specific regions of these elements can form a stable stem structure which is involved in the formation of RNA-protein complexes. By employing electrophoretic mobility shift assays, two complexes have been identified in cytoplasmic extracts of Hep3B cells. The formation of these complexes is related to the growth conditions of the cells and is correlated with the regulation of IGF-II mRNA levels. Our data suggest that, depending on whether serum is present or absent, a transition from one complex to the other occurs. A decrease in the IGF-II mRNA level is also observed when IGF-I or IGF-II is added to serum-deprived Hep3B cells, possibly providing a feedback mechanism for IGF-II production. The serum-induced degradation of IGF-II mRNAs does not require de novo protein synthesis, and is abolished by rapamycin, an inhibitor of p70 S6 kinase.

Base Sequence↗
PubMed1996

The cis-acting elements involved in endonucleolytic cleavage of the 3' UTR of human IGF-II mRNAs bind a 50 kDa protein.

Site-specific cleavage of human insulin-like growth factor II mRNAs requires two cis-acting elements, I and II, that are both located in the 3' untranslated region and separated by almost 2 kb. These elements can interact and form a stable RNA-RNA stem structure. In this study we have initiated the investigation of transacting factors involved in the cleavage of IGF-II mRNAs. The products of the cleavage reaction accumulate in the cytoplasm, suggesting that cleavage occurs in this cellular compartment. By electrophoretic mobility shift assays, we have identified a cytoplasmic protein with an apparent molecular weight of 48-50 kDa, IGF-II cleavage unit binding protein (ICU-BP), that binds to the stem structure formed by interaction of parts of the cis-acting elements I and II. The binding is resistant to high K+ concentrations and is dependent on Mg2+. In addition, ICU-BP binding is dependent on the cell density and correlates inversely with the IGM-II mRNA levels. In vivo cross-linking data show that this protein is associated with IGF-II mRNAs in vivo.

Base Sequence↗
PubMed1995

Long-range RNA interaction of two sequence elements required for endonucleolytic cleavage of human insulin-like growth factor II mRNAs.

Human insulin-like growth factor II (IGF-II) mRNAs are subject to site-specific endonucleolytic cleavage in the 3' untranslated region, leading to an unstable 5' cleavage product containing the IGF-II coding region and a very stable 3' cleavage product of 1.8 kb. This endonucleolytic cleavage is most probably the first and rate-limiting step in degradation of IGF-II mRNAs. Two sequence elements within the 3' untranslated region are required for cleavage: element I, located approximately 2 kb upstream of the cleavage site, and element II, encompassing the cleavage site itself. We have identified a stable double-stranded RNA stem structure (delta G = -100 kcal/mol [418.4 kJ/mol]) that can be formed between element I and a region downstream of the cleavage site in element II. This structure is conserved among human, rat, and mouse mRNAs. Detailed analysis of the requirements for cleavage shows that the relative position of the elements is not essential for cleavage. Furthermore, the distance between the coding region and the cleavage site does not affect the cleavage reaction. Mutational analysis of the long-range RNA-RNA interaction shows that not only the double-stranded character but also the sequence of the stable RNA stem is important for cleavage.

Animals↗
PubMed1993

Transcriptional and post-transcriptional regulation of the human IGF-II gene expression.

The human insulin-like growth factor II (IGF-II) gene consists of nine exons and has four promoters (P1-4). The promoters exhibit a tissue-specific and developmental stage-dependent expression pattern. In fetal liver promoters P2-4 are expressed, but after birth these promoters are shut off and another promoter, P1, is activated. We have investigated some properties of the human promoters P1 and P3 and identified a number of sequence elements, that are recognized by transcription factors. Promoter P1 is stimulated by the liver-enriched transcription factors C/EBP and LAP, whereas in the proximal region of P3 we have identified several elements that are recognized by transcription factors, including krox20/egr2 and krox24/erg1. Besides transcriptional regulation of expression also regulation at the post-transcriptional level occurs. We have found that the IGF-II mRNAs are subjected to site-specific endonucleolytic cleavage yielding a labile 5' specific fragment and a stable polyadenylated 3' specific cleavage product of 1.8 kb. Two widely separated sequence elements within the last exon were identified that are able to interact and yield a double-stranded stem structure. It is likely that this structure is essential for post-transcriptional cleavage of IGF-II mRNAs.

Animals↗
PubMed1992

Site-specific cleavage of IGF-II mRNAs requires sequence elements from two distinct regions of the IGF-II gene.

The human insulin-like growth factor II (IGF-II) gene constitutes a complex transcriptional unit that contains nine exons and four promoters. Expression of the IGF-II gene yields a family of mRNAs that all encode prepro-IGF-II. In addition, a stable 1.8 kb RNA is formed that is derived from the 3' untranslated region of exon 9. Recently, we have shown that this RNA species arises by site-specific endonucleolytic cleavage of IGF-II mRNAs and not by transcription from a separate promoter. In the present study we establish that two widely separated sequence elements of approximately 300 nucleotides, both located within exon 9, are required for this cleavage reaction. The first element encompasses about 200 nucleotides upstream and 100 nucleotides downstream of the cleavage site, while the second element is located within a region of 330 nucleotides about 2 kb upstream of the cleavage site. Interestingly, site-specific cleavage also occurred when a fragment from exon 9 of the IGF-II gene containing these two elements was inserted into the 3' untranslated part of the beta-globin gene. Apparently, the expressed hybrid beta-globin-IGF-II mRNA contains all the regulatory elements to confer site-specific endonucleolytic cleavage.

Alternative Splicing↗
PubMed1978

[Fixing the time and date of photograph (author's transl)].

A system is described to obtain on photographs and slides an automatic printout of patient number, eye and time. The time is recorded in minutes, seconds and tenth of seconds or in minutes and seconds. The time-recording can be switched off if only patient and eye identification is needed.

Documentation↗
PubMed1977

Vertical motor fusion.

An analysis is given of the eye movements which take place in vertical fusion. These movements are compared with the movements that occur in horizontal fusion. The differences and similarities that can lead to a model are stressed.

Eye Movements↗