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C L Masters

Publications and source records attributed to C L Masters.

At least 235 records · Page 13Linked to original sources
PubMed1988

Neuropathology of unconventional virus infections: molecular pathology of spongiform change and amyloid plaque deposition.

To the triad of neuronal loss, gliosis and spongiform change as characteristic morphological changes associated with infection of the central nervous system, one can now add the presence of scrapie-associated filaments (SAF)/PrP rods. While the host's immune response is conspicuous by its absence, the vigorous astrocytic response is presumptive evidence of the host's ability to recognize and respond to the primary neuronal insult. We assume that the spongiform change and vacuolation of neurons are of fundamental importance in the pathogenesis of the disease, realizing that neither is specific or essential for the replication of the infectious agent. The topographical distribution of lesions is partly explained by the portal of entry and retrograde spread of the virus. The temporal progression of the lesions is more clearly determined by the host genes, best illustrated by studies of the incubation period. The molecular basis of the spongiform change is unknown but it is presumed to involve some disturbance of membrane metabolism. The recognition of PrP as a membrane glycoprotein invites proposals for its role in the development of these spongiform lesions. Extracellular amyloid occurs as plaques or congophilic angiopathy in some instances, and provides the best evidence that Alzheimer's disease (AD) is in some way related to the unconventional virus diseases. However, the protein subunit (A4) of the amyloid fibril in AD and its precursor are quite distinct from the PrP subunit which constitutes the amyloid fibril in these infectious diseases. It is still unclear whether the PrP subunit in the SAF has exactly the same composition as in the extracellular amyloid fibril. Our results suggest that only a fragment of the PrP molecule is the major constituent of the extracellular fibril. Since both PrP and A4 are derived from membrane glycoproteins, the elucidation of their normal function is likely to lead to a better understanding of the spongiform and amyloidogenic lesions in these diseases.

Alzheimer Disease↗
PubMed1988

Rett syndrome: abnormal membrane-bound lamellated inclusions in neurons and oligodendroglia.

The brain biopsy of a patient with Rett syndrome showed light microscopic evidence of white matter disease. Ultrastructurally, many neurons and oligodendroglia contained membrane-bound electron-dense inclusions with a distinct lamellar and granular substructure. This substructure suggests that part of these inclusions are derived from phospholipid. If confirmed in other cases of Rett syndrome, the neurochemical study of these inclusions may contribute to an understanding of this disorder.

Brain↗
PubMed1988

Localization of the putative precursor of Alzheimer's disease-specific amyloid at nuclear envelopes of adult human muscle.

Cloning and sequence analysis revealed the putative amyloid A4 precursor (pre-A4) of Alzheimer's disease to have characteristics of a membrane-spanning glycoprotein. In addition to brain, pre-A4 mRNA was found in adult human muscle and other tissues. We demonstrate by in situ hybridization that pre-A4 mRNA is present in adult human muscle, in cultured human myoblasts and myotubes. Immunofluorescence with antipeptide antibodies shows the putative pre-A4 protein to be expressed in adult human muscle and associated with some but not all nuclear envelopes. Despite high levels of a single 3.5-kb pre-A4 mRNA species in cultured myoblasts and myotubes, the presence of putative pre-A4 protein could not be detected by immunofluorescence. This suggests that putative pre-A4 protein is stabilized and therefore functioning in the innervated muscle tissue but not in developing, i.e. non-innervated cultured muscle cells. The selective localization of the protein on distinct nuclear envelopes could reflect an interaction with motor endplates.

Adult↗
PubMed1988

Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease.

The precursor of the Alzheimer's disease-specific amyloid A4 protein is an integral, glycosylated membrane protein which spans the bilayer once. The carboxy-terminal domain of 47 residues was located at the cytoplasmic site of the membrane. The three domains following the transient signal sequence of 17 residues face the opposite side of the membrane. The C-terminal 100 residues of the precursor comprising the amyloid A4 part and the cytoplasmic domain have a high tendency to aggregate, and proteinase K treatment results in peptides of the size of amyloid A4. This finding suggests that there is a precursor-product relationship between precursor and amyloid A4 and we conclude that besides proteolytic cleavage other events such as post-translational modification and membrane injury are primary events that precede the release of the small aggregating amyloid A4 subunit.

Alzheimer Disease↗
PubMed1988

The promoter of Alzheimer's disease amyloid A4 precursor gene.

The promoter of the gene for the human precursor of Alzheimer's disease A4 amyloid protein (PAD gene) resembles promoters of housekeeping genes. It lacks a typical TATA box and shows a high GC content of 72% in a DNA region that confers promoter activity to a reporter gene in an in vivo assay. Transcription initiates at multiple sites. Sequences homologous to the consensus binding sites of transcription factor AP-1 and the heat shock control element binding protein were found upstream of the RNA start sites. Six copies of a 9-bp-long GC-rich element are located between positions -200 and -100. A protein--DNA interaction could be mapped to this element. The 3.8 kb of the 5' region of the PAD gene include two Alu-type repetitive sequences. These findings suggest that four mechanisms may participate in the regulation of the PAD gene and could be of relevance for the progression of amyloid deposition in Alzheimer's disease.

Alzheimer Disease↗
PubMed1988

A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques.

The histologic diagnosis of Alzheimer's disease (AD) might be aided if a more sensitive marker of aberrant A4 amyloid protein deposition were available. We screened a sample of aged brains, using immunocytochemical methods to detect the A4 protein deposition, and found that, in comparison with conventional histologic techniques (silver impregnation and Congo red), immunocytochemistry is more sensitive and allows an easier demarcation between "normal" and "abnormal." If A4 protein deposition is accepted as a definitive marker for AD, then the age-related prevalence of AD increases dramatically. To what degree these prevalence rates are reflected in clinically detectable impairment of higher cortical function remains to be determined.

Aged↗
PubMed1987

Neuronal origin of cerebral amyloidogenic proteins: their role in Alzheimer's disease and unconventional virus diseases of the nervous system.

The protein component of Alzheimer's disease amyloid (neurofibrillary tangles, amyloid plaque cores and congophilic angiopathy) is an aggregated polypeptide with a subunit mass of approximately 4 kDa (the A4 monomer). The aggregational properties of this monomer may explain the amyloidogenic nature of the protein: the native monomer forms dimers, tetramers and higher oligomeric species which are dependent on pH, ionic strength and concentration; the synthetic peptide corresponding to residues 1-28 spontaneously forms fibrils in vitro. Based on the degree of N-terminal heterogeneity, the A4 monomer aggregates first in neurons and later in the extracellular space. Using antisera raised against synthetic peptides, we can demonstrate that the N-terminus contains an epitope for neurofibrillary tangles, and the inner region of the molecule contains an epitope for the extracellular amyloid fibrils. There is a non-protein component of the amyloid (inorganic residues of aluminium silicate) which may be important in the deposition of the amyloid fibrils. There are several intriguing similarities between the amyloid fibrils and proteins of Alzheimer's disease when compared to the scrapie-associated filaments and proteins of the unconventional virus diseases (scrapie, kuru, Creutzfeldt-Jakob disease). Although there is no sequence homology between the proteins, we suspect they are formed as a result of similar biochemical processes. If the scrapie proteins and filaments are an integral part of the infectious agent, it follows that Alzheimer's disease is also an infectious process similar to scrapie. As they are host-encoded proteins, it is still feasible that both types are pathological by-products of independent diseases.

Alzheimer Disease↗
PubMed1987

Culture of mouse brain capillary endothelial cell lines that express factor VIII, gamma-glutamyl transpeptidase, and form junctional complexes in vitro.

The isolation and culture of cell lines from mouse brain capillary endothelium (MBE) is described. Cells migrating from collagenase-treated capillary fragments proliferated rapidly in the 1st wk of culture forming large epithelioid cobblestonelike colonies. The cells showed only marginal proliferation after 2 to 3 wk in culture, until peripheral cells migrated away from the colony which exhibited a marked degree of proliferation. These cells were trypsinized and subcultured to confluence. The cells can be maintained for well over 40 passages and seem to retain their endothelial morphology. The endothelial origin of these cells was demonstrated by positive immunoperoxidase reactivity with Factor VIII-related antigen, specific binding of Bandeiraea simplicifolia lectin and gamma-glutamyl transpeptidase activity. Electron microscopic examination of the MBE cells showed junctional complexes including intermediate junctions, but no tight junctions. The overall ultrastructure indicates that a degree of dedifferentiation has occurred, the cells ultrastructurally resembling immature endothelium. An earlier investigation of cultured mouse brain endothelial cells reported a cell line that had lost many functional and structural characteristics. Our study demonstrates, as the previous one, that a certain degree of dedifferentiation needs to occur if MBE cells are to be maintained for long-term culture. However, the degree of dedifferentiation seems to be variable, depending in part on the culture conditions employed.

Animals↗
PubMed1987

Amyloid of neurofibrillary tangles of Guamanian parkinsonism-dementia and Alzheimer disease share identical amino acid sequence.

The presence of abundant intraneuronal amyloid in the form of neurofibrillary tangles (NFT) in the brains of Guamanian parkinsonism-dementia patients and the absence of extraneuronal amyloid in the form of vascular amyloid deposits or senile plaques permit the purification of NFT without contamination with extraneuronal amyloid. Thus, we have isolated and determined the amino acid sequence of the polypeptide subunit of the amyloid fibrils of these NFT and describe their ultrastructure. The NFT, which consist of single and paired helical filaments, similar to those of Alzheimer disease, and occasionally triple helical filaments, are composed of multimeric aggregates of a polypeptide of 42 amino acids (A4 protein). The relative molecular mass of the subunit protein, 4.0-4.5 kDa, is the same as the molecular mass of the amyloid of NFT, of the amyloid plaque cores, and of vascular amyloid deposits in Alzheimer disease and Down syndrome; the sequence of 15 amino acid residues at the N-terminus of the amyloid fibrils in the NFT of Guamanian parkinsonism-dementia is identical to that of the amyloid of NFT, amyloid plaque cores, and cerebrovascular deposits in Alzheimer disease and Down syndrome. Furthermore, the heterogeneity, or variation in polypeptide length, of the N-terminus of the amyloid of Guamanian parkinsonism-dementia is the same as in Alzheimer disease and Down syndrome. Our observations indicate that the brain amyloids of these diseases have a common subunit protein, which would also indicate a common pathogenesis.

Aged↗
PubMed1986

Regulation of liver and brain hexose monophosphate dehydrogenases by insulin and dietary intake in the female rat.

Liver glucose 6-phosphate dehydrogenase and phosphogluconate dehydrogenase activities were significantly decreased in both diabetic and fasted rats. Treatment of diabetic rats with insulin resulted in liver glucose 6-phosphate dehydrogenase and phosphogluconate dehydrogenase activities that were significantly greater than controls. Insulin promoted an increase in food consumption that was blocked by adrenaline. Insulin, when administered together with adrenaline, restored hepatic glucose 6-phosphate dehydrogenase and phosphogluconate dehydrogenase activities of diabetic animals to control values, without altering food consumption. Brain glucose 6-phosphate dehydrogenase and phosphogluconate dehydrogenase activities were not significantly altered by either dietary restriction, diabetes or insulin treatment. These results demonstrate a dissociation between the action of insulin on hepatic glucose 6-phosphate dehydrogenase activity and its action to increase food intake.

Animals↗
PubMed1986

Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer's disease may reflect oxidative stress.

The activities of the hexose monophosphate pathway enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were measured at autopsy in control and Alzheimer's disease brains. Enzyme activities did not vary between different areas of brain and were unaltered by age. In Alzheimer's disease, the activities of both enzymes were increased, the glucose-6-phosphate dehydrogenase activity being almost double the activity of normal controls. We propose that this increased enzyme activity is a response to elevated brain peroxide metabolism.

Adult↗
PubMed1986

Observations on the clinical presentations and the neuropathological findings of amyotrophic lateral sclerosis in Australia and Guam.

Among 20 consecutive autopsies of amyotrophic lateral sclerosis (ALS) occurring in Caucasians in Western Australia (WA), 85% were males. The median age of onset was 58.9 years and the average duration of illness was 2.4 years. Twenty-two randomly selected ALS occurring among natives in Guam also showed a male predominance of 75%, younger age of onset (median 48.5 years) and longer survival period (median 3.4 years). 45% of the WA patients presented with bulbar involvement at the time of first examination. These patients had the lowest median survival period of 1.5 years when compared with the other forms of ALS, the classic upper and lower motor system involvement and progressive muscular atrophy. Theneuropathologic lesions of ALS in WA and Guam were similar with the exception that neurofibrillary tangles were frequently present in the Guamanian brains. In 14%, neuronal loss, gliosis and frequency of tangles in the cerebral cortex especially in Ammon's horn, substantia nigra, and locus ceruleus, were sufficiently severe to indicate the coexistence of another disorder, Parkinsonism-Dementia Complex. This condition was not clinically recognized. In the WA cases only one patient had tangles in the brain and he had concurrent Alzheimers disease. While senile plaques were present in this patient they were usually absent in the Guamanian brains.

Adolescent↗
PubMed1985

Loop arrays in mouse brain demonstrated with antisera to cytokeratins and monoclonal antibodies to several classes of intermediate filaments: strain differences and developmental expression.

Some monoclonal antibodies raised against mouse brain antigens display a novel loop array apparently localized within the cytoplasm of neurons in fresh frozen sections of adult mouse brain. By indirect immunofluorescence, these loops are detectable in the cerebral cortex, thalamus, brainstem, and are particularly striking in association with pyramidal neurons of the hippocampus. The loops are also seen with polyclonal antibodies to the cytokeratin class of intermediate filaments. The antibodies which react with these loops also react with ependymal cells. Western blot analysis of crude insoluble cytoskeletal components of mouse brain with antibodies of cytokeratins confirm the presence of reactive bands in the range of 40-60 kdalton, appropriate in molecular weight for this class of cytoskeletal filaments. This evidence suggests that the loops share antigenic determinants with non-neural cytokeratins. During development, immunoreactive structures are first seen as small punctate or curvilinear profiles, which change into a loop array at approximately 14 days postnatal age in several mouse strains. However, in 8 of 15 different mouse strains, these immature punctate profiles remain without morphological alteration to loops throughout adult age. The F1 crosses between strains with and without the loops develop loops, but on average they are of smaller size than in the positive parent.

Animals↗
PubMed1985

Regulation of the multiple molecular forms of rat liver glucose 6-phosphate dehydrogenase by insulin and dietary restriction.

Insulin treatment of virgin female rats increased the hepatic activity of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase to levels 3.4 and 1.5 fold higher than controls. The increase in glucose 6-phosphate dehydrogenase activity was attributed to increased activity of all three dimer species. Thus dimer bands, 1, 2 and 3 of insulin-treated animals were 5, 3 and 2-fold higher respectively than controls. The activity of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase decreased with fasting to 55% and 72% respectively of controls. The decrease in glucose 6-phosphate dehydrogenase activity reflected a lower activity of dimer bands 2 and 3 only, which were 62% and 39% of control activity respectively after three days fasting. A shift towards band 1 was observed under both conditions of starvation as well as under conditions of insulin treatment.

Animals↗
PubMed1985

Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels.

The protein component of Alzheimer's disease amyloid [neurofibrillary tangles (NFT), amyloid plaque core and congophilic angiopathy] is an aggregated polypeptide with a subunit mass of 4 kd (the A4 monomer). Based on the degree of N-terminal heterogeneity, the amyloid is first deposited in the neuron, and later in the extracellular space. Using antisera raised against synthetic peptides, we show that the N terminus of A4 (residues 1-11) contains an epitope for neurofibrillary tangles, and the inner region of the molecule (residues 11-23) contains an epitope for plaque cores and vascular amyloid. The non-protein component of the amyloid (aluminum silicate) may form the basis for the deposition or amplification (possible self-replication) of the aggregated amyloid protein. The amyloid of Alzheimer's disease is similar in subunit size, composition but not sequence to the scrapie-associated fibril and its constituent polypeptides. The sequence and composition of NFT are not homologous to those of any of the known components of normal neurofilaments.

Alzheimer Disease↗
PubMed1985

Amyloid plaque core protein in Alzheimer disease and Down syndrome.

We have purified and characterized the cerebral amyloid protein that forms the plaque core in Alzheimer disease and in aged individuals with Down syndrome. The protein consists of multimeric aggregates of a polypeptide of about 40 residues (4 kDa). The amino acid composition, molecular mass, and NH2-terminal sequence of this amyloid protein are almost identical to those described for the amyloid deposited in the congophilic angiopathy of Alzheimer disease and Down syndrome, but the plaque core proteins have ragged NH2 termini. The shared 4-kDa subunit indicates a common origin for the amyloids of the plaque core and of the congophilic angiopathy. There are superficial resemblances between the solubility characteristics of the plaque core and some of the properties of scrapie infectivity, but there are no similarities in amino acid sequences between the plaque core and scrapie polypeptides.

Alzheimer Disease↗