Neurodegeneration最新文献

{"title":"Characterization of Appican, the Chondroitin Sulfate Proteoglycan Form of the Alzheimer Amyloid Precursor Protein","authors":"Menelas N. Pangalos,&nbsp;Junichi Shioi,&nbsp;Spiros Efthimiopoulos,&nbsp;Anfan Wu,&nbsp;Nikolaos K. Robakis","doi":"10.1006/neur.1996.0061","DOIUrl":"10.1006/neur.1996.0061","url":null,"abstract":"<div><p>In this report we focus on the characterization of appican, the chondroitin sulfate proteoglycan form of amyloid precursor protein (APP), and the role that it and other proteoglycans may play in AD. Appican is expressed by certain transformed cell lines of neural origin, namely C6 cells and N2a neuroblastomas. It is detected in both human and rat brain and in primary cultures is expressed by astrocytes, but not neurons. The core protein of appican has been shown to be an alternatively spliced isoform of APP, lacking exon 15 of the APP gene, originally identified in leukocytes (L-APP). Splicing out of exon 15 results in the joining of exons 14 and 16, and formation of an Asp-Xaa-Ser-Gly consensus sequence for chondroitin sulfate chain attachment to serine 619 of L-APP, which lies 16 amino acids upstream of the A β peptide sequence. Mutation of this serine residue to an alanine prevented chondroitin sulfate chain addition to the core protein. Levels of appican expression could be regulated by growth conditions independently of APP, suggesting that these molecules may serve distinct physiological roles within the cell. Morphological changes were also observed in both astrocytic and transformed cell cultures, that appeared to reflect changes in levels of appican expression. Preliminary data suggest that appican may be a strong cell adhesion molecule. Transfected C6 glioma cells overexpressing appican remained attached to tissue culture dishes markedly better than either C6 cells over-expressing exon-15 containing APP or WT C6 cells. Appican-enriched extracellular matrix (ECM) was also observed to serve as a much better substrate for attachment of N2a neuroblastomas, pheocromocytoma PC12 cells and primary astrocytes compared to APP enriched ECM.</p></div>","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 445-451"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20065853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monoamine Oxidase Molecular Activity in Platelets of Parkinsonian and Demented Patients","authors":"P. Bongioanni ,&nbsp;C. Mondino ,&nbsp;B. Boccardi ,&nbsp;M. Borgna ,&nbsp;M. Castagna","doi":"10.1006/neur.1996.0047","DOIUrl":"10.1006/neur.1996.0047","url":null,"abstract":"<div><p>Platelet monoamine oxidase activity levels have been evaluated in several neuropsychiatric disorders, to identify biochemical markers for pathological brain functioning. In the present work, we assayed both total and molecular monoamine oxidase activity in platelets of parkinsonian and demented patients: both showed significantly higher enzyme activity values than healthy controls. Thus, high platelet monoamine oxidase activity levels seem to be related to an increased intrinsic activity of single enzyme molecules. A significant positive correlation was found between platelet monoamine oxidase activity and severity of illness in both disorders: monoamine oxidase activity, therefore, may be considered as a state-dependent marker for neuro-degeneration. Such findings are discussed with reference to central nervous system biochemical abnormalities in parkinsonian and demented subjects; it might be that in both Parkinson's Disease and in dementia of Alzheimer type some central biochemical changes are reflected in certain peripheral tissues (thrombocytes, for instance), or that a systemic derangement accompanies the cerebral involvement.</p></div>","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 351-357"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20065901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Somatostatin, its Molecular Forms and Monoaminergic Transmitter Metabolites in Binswanger's Disease. Neurochemical-Neuropathological Considerations","authors":"M. Strittmatter ,&nbsp;M.T. Grauer ,&nbsp;G.F. Hamann ,&nbsp;H. Cramer ,&nbsp;K. Schimrigk","doi":"10.1006/neur.1996.0048","DOIUrl":"10.1006/neur.1996.0048","url":null,"abstract":"<div><p>Cerebrospinal fluid (CSF) concentrations of somatostatin-like immunoreactivity (SLI), high molecular weight form somatostatin (HMV-SST), somatostatin-25/28 (SST-25/28), somatostatin–14 (SST-14), Des-ala-somatostatin (Des-ala-SST), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5–HIAA) were measured in 21 patients with Binswanger's dementia (BD). Patients were classed into three stages of intellectual deterioration according to the Global de-terioration scale (GDS). Levels of SLI were significantly decreased in patients suffering from BD, compared to a control group (19.7 ± 11.6 fmol/ml vs. 30.5 ± 8.6 fmol/ml,<em>P</em>&lt; 0.01). There was no correlation with dementia scores (<em>r</em>= 0.34,<em>P</em>= 0.51). The observed qualitative and quantitative changes in the molecular pattern of SLI suggest the occurrence of a dysregulated posttranslational processing in patients with BD. Whereas 5-HIAA levels were not significantly changed in patients with BD, HVA was significantly increased in mild to moderate dementia (GDS 2-4) and significantly decreased in severe cases (GDS 7) (224.3 ± 69.9 nmol/ml vs. 364.9 ± 103.8 nmol/ml,<em>P</em>&lt; 0.01); this correlated with dementia scores (<em>r</em>= −0.59,<em>P</em>&lt; 0.01). The existence of significant correlations between SLI, 5-HIAA and HVA in BD point to a heterogeneous and generalized neurochemical process affecting several transmitter systems and functions.</p></div>","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 359-366"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20065902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer's Disease: From Acetylcholine to β–Amyloid","authors":"A.M. Palmer,&nbsp;P.T. Francis","doi":"10.1006/neur.1996.0050","DOIUrl":"10.1006/neur.1996.0050","url":null,"abstract":"","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 379-380"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20065904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Presenilin–1 is Processed into Two Major Cleavage Products in Neuronal Cell Lines","authors":"Robin V. Ward ,&nbsp;John B. Davis ,&nbsp;Carol W. Gray ,&nbsp;Amanda J.L. Barton ,&nbsp;Laura G. Bresciani ,&nbsp;Matilde Caivano ,&nbsp;Vivienne F. Murphy ,&nbsp;Karen Duff ,&nbsp;Michael Hutton ,&nbsp;John Hardy ,&nbsp;Gareth W. Roberts ,&nbsp;Eric H. Karran","doi":"10.1006/neur.1996.0040","DOIUrl":"10.1006/neur.1996.0040","url":null,"abstract":"<div><p>Presenilin 1 (PS–1) has been identified as the protein encoded by the chromosome 14 locus that, when mutated, leads to familial Alzheimer's disease (FAD). Using PS–1 transfected SHSY5Y neuroblastoma cells, we have demonstrated by immunodetection, using polyclonal antibodies, that PS–1 is processed to give two fragments: an N–terminal 28 kDa fragment, and a C–terminal 18 kDa fragment. In a number of non-transfected cell types, most PS–1 is detected as the cleaved products. The molecular weights of the PS–1 cleavage products suggest that the cleavage point will most probably be within a region of the hydrophilic loop domain coded for by either exon 8 or 9 of the PS–1 gene. The clustering of FAD mutations within exon 8 strongly suggests that it encodes a key functional domain. It seems likely that the cleavage of PS–1 is crucial to some aspect of its functionality. An understanding of this process will give insights into the pathology of AD, and may offer new opportunities for therapeutic intervention.</p></div>","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 293-298"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20066755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Midbrain Dopaminergic Neurons in the Mouse that Contain Calbindin-D28kExhibit Reduced Vulnerability to MPTP-induced Neurodegeneration","authors":"Chang-Lin Liang ,&nbsp;Christopher M. Sinton ,&nbsp;Patricia K. Sonsalla ,&nbsp;Dwight C. German","doi":"10.1006/neur.1996.0042","DOIUrl":"10.1006/neur.1996.0042","url":null,"abstract":"<div><p>The calcium-binding protein calbindin-D_28k(CB) is located in midbrain dopaminergic (DA) neurons that are less vulnerable to degeneration in Parkinson's disease and in an animal model of the disorder, the MPTP-treated monkey. The present study sought to determine whether CB-containing DA neurons are also less vulnerable to degeneration in the MPTP-treated mouse. Double-labelling immunocytochemical staining and computer imaging techniques were employed to map and quantify the tyrosine hydroxylase-, CB- and CB-containing tyrosine hydroxylase neurons in portions of nucleus A9 and nucleus A10 (ventral tegmental area and central linear nucleus) following MPTP treatment in the C57BL/6 mouse. A cumulative dose of 140 mg/kg MPTP produced a significantly greater loss of DA neurons that lack CB in both nucleus A9 (71 ± 4%) and the ventral tegmental area (70 ± 4%), compared to the loss of DA neurons that contain CB (44 ± 6% and 25 ± 14%, respectively). In the central linear nucleus there was no loss of CB-containing DA neurons. These data demonstrate that the presence of CB in midbrain DA neurons identifies a population of cells in the mouse that are less vulnerable to MPTP-induced degeneration. The mouse, therefore, can serve as a useful model in which to investigate the putative neuroprotective effects of CB in an animal model of Parkinson's disease.</p></div>","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 313-318"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20066757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Features of Sporadic and Familial Alzheimer's Disease","authors":"M.N. Rossor ,&nbsp;N.C. Fox ,&nbsp;P.A. Freeborough ,&nbsp;R.J. Harvey","doi":"10.1006/neur.1996.0052","DOIUrl":"10.1006/neur.1996.0052","url":null,"abstract":"<div><p>Alzheimer's disease is increasingly seen as an heterogeneous disorder with a variety of molecular pathologies converging on a final common pathway of abnormal amyloid deposition and tau phosphorylation. These result in the appearance of the senile plaques and neurofibrillary tangles and in the subsequent development of a cortical dementia with a prominent memory deficit, reflecting the regional distribution of pathology. Age and mode of onset, additional neurological features and family history have all been used as a basis for classification. A family history has proved most robust with the identification of three genetic loci associated with autosomal dominant familial Alzheimer's disease (FAD). Genetically defined pedigrees are important for exploring the relationships between specific molecular pathology and clinical phenotype and, by following at risk individuals, identifying the earliest features.</p></div>","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 393-397"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20065906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyramidal Neurone Modulation: A Therapeutic Target for Alzheimer's Disease","authors":"Paul T. Francis","doi":"10.1006/neur.1996.0063","DOIUrl":"10.1006/neur.1996.0063","url":null,"abstract":"<div><p>It is proposed that pyramidal neurones are central to the pathogenesis and cognitive dysfunction of AD on the basis that they are the site of tangle formation and the mismetabolism of APP and degenerate, and that such cells are the focus of neurotransmitter abnormalities. Anatomical studies in animal and human brain are revealing which neurotransmitter receptors are present on populations of pyramidal neurones and a microdialysis approach has demonstrated the ability of such receptors to alter neuronal activity. Specifically, it is proposed that cholinomi-metics used for the symptomatic treatment of AD may work by influencing the activity of pyramidal neurones and that this action may be potentiated by a 5-HT_1Aantagonist. The contribution of pyramidal neurone transmission failure to the spread of pathology in AD is the subject of continuing investigation.</p></div>","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 461-465"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20066521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetylcholine Receptor Targets on Cortical Pyramidal Neurones as Targets for Alzheimer's Therapy","authors":"Iain P. Chessell","doi":"10.1006/neur.1996.0062","DOIUrl":"10.1006/neur.1996.0062","url":null,"abstract":"<div><p>Experimental lesions using the retrogradely transported toxin, volkensin, have been used in conjunction with autoradiography to investigate the cellular localization of 5–HT_1A, muscarinic M₁and nicotinic receptors. Selective destruction of neocortical pyramidal neurones forming the corticostriatal or corticocortical pathways was achieved by intrastriatal or intracortical injection of volkensin. Selective destruction of layer V corticostriatal neurones was accompanied by loss of binding in the cortex to 5–HT_1Aand muscarinic M₁receptors, and an upregulation of [³H] nicotine binding contralateral to the pyramidal cell loss. Destruction of corticocortical neurones was accompanied by loss of binding to muscarinic and nicotinic receptors. The presence of these cholinoceptors on corticocortical neurones was confirmed by recording carbachol-induced depolarizations from a novel cortical brain slice preparation. It is proposed that cholinoceptors represent a consistent marker for neocortical pyramidal cells, and as such are viable targets for the continuing development of therapies designed to ameliorate the cortical hypoactivity observed in Alzheimer's disease. Ligands for these receptors may also be suitable for positron emission tomography to assess pyramidal neurone numbers in suspected Alzheimer's disease.</p></div>","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 453-459"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20065854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motor Neurone Disease-inclusion Dementia","authors":"Matthew Jackson ,&nbsp;Graham Lennox ,&nbsp;James Lowe","doi":"10.1006/neur.1996.0046","DOIUrl":"10.1006/neur.1996.0046","url":null,"abstract":"<div><p>We describe nine patients, five women and four men (age at death 58–83 years), who developed isolated progressive frontotemporal dementia over 4 to 12 years. These cases represent nine of the 385 (2.3%) cases from a series of autopsy cases of dementia in a large teaching hospital. One had a mother with a history of frontotemporal dementia and marked frontal lobe atrophy. Another had multiple affected family members with frontotemporal dementia, motor neurone disease or both. None of the nine had clinical evidence of either an upper or lower motor neurone disorder. In each case neuropathological examination revealed cortical pathology identical to that described previously as typical of dementia associated with motor neurone disease. There was variable macroscopic atrophy and neuronal loss in the frontal and temporal lobes. All cases had cortical microvacuolation, in seven limited to cortical layer II, and transcortical in two. There was variable cortical and subcortical gliosis. Intraneuronal ubiquitin-immunoreactive inclusions, characteristic of the extra-motor involvement of motor neurone disease, were found in the hippocampal dentate granule cells and residual neurones in layer II of the frontotemporal cortex of all cases. Similar inclusions were also seen in the nucleus ambiguus of three cases. The hypoglossal nuclei showed no neuronal loss, gliosis or ubiquitin-immunoreactive inclusions. Ubiquitin-immunoreactive dystrophic neurites were detected within affected cortex, being most conspicuous in layer II in areas containing microvacuolation. Dystrophic neurites were not detected in subcortical structures. Spinal cords were unavailable for examination because of limited autopsy consent. The finding of intraneuronal ubiquitin-immunoreactive inclusions characteristic of motor neurone disease in patients with frontotemporal dementia, without clinical or pathological evidence of motor system degeneration, extends the clinical spectrum of diseases associated with such inclusions. We propose the term motor neurone disease-inclusion dementia (MNDID) for these cases.</p></div>","PeriodicalId":19127,"journal":{"name":"Neurodegeneration","volume":"5 4","pages":"Pages 339-350"},"PeriodicalIF":0.0,"publicationDate":"1996-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/neur.1996.0046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20065900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}