Apolipoprotein E-epsilon 4 allele and Alzheimer's disease.
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Age Factors↗
Biomedical subjects
C Masters
Publications and source records attributed to C Masters.
Ontogenic activities and interactions of the lactate dehydrogenase isozymes with cellular structure in the guinea pig.
The LDH activities and isozyme distributions associated with soluble and particulate fractions of five major tissues have been followed during the development of the guinea pig. Evidence has been provided for an appreciable degree of interaction between LDH and cellular structure in all these tissues (liver, kidney, skeletal muscle, brain and heart) at all stages of development, but particularly in the early foetal stages. These data have been discussed in relation to the nature and extent of this binding and the correlations with the metabolic emphases in these tissue situations during development.
Animals↗
Amyloidogenicity of beta A4 and beta A4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation.
Previously we have shown that the COOH-terminal 100 residues (A4CT) of the amyloid protein precursor (APP), which carry the sequence of the amyloid beta A4 protein of Alzheimer's disease at N-terminal position, form highly insoluble aggregates if expressed in the rabbit reticulocyte lysate and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (Dyrks, T., Weidemann, A., Multhaup, G., Salbaum, J.M., Lemaire, H.-G., Kang, J., Müller-Hill, B., Masters, C. L., and Beyreuther, K. (1988) EMBO J. 7, 949-957). Here we report that aggregation of this COOH-terminal APP fragment A4CT and also of beta A4 itself depends on additional factors. In contrast to the reticulocyte expression system, expression of A4CT and beta A4 in the wheat germ expression system resulted in only monomeric forms. We have identified the factors which are capable of transforming both soluble A4CT and beta A4 into insoluble and aggregating molecules. Monomeric A4CT or beta A4 expressed in the wheat germ lysate could be transformed into aggregating molecules by the addition of metal-catalyzed oxidation systems. The addition of radical scavengers such as ascorbic acid, trolox, and amino acids prevented the aggregation process induced by the radical initiators. Thus, the aggregation of amyloidogenic APP fragments if analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis requires amino acid oxidation and protein cross-linking induced by radical generation systems.
Amyloid beta-Protein Precursor↗
Membrane inserted APP fragments containing the beta A4 sequence of Alzheimer's disease do not aggregate.
Previously we have shown that the COOH-terminal fragment (A4CT) of the Alzheimer amyloid protein precursor (APP), which at the NH2-terminus carries the sequence of the amyloid beta A4 protein, forms highly insoluble aggregates [EMBO J. (1988) 7, 949-957]. Here we report that aggregation is prevented if A4CT is expressed in vitro with a signal sequence at the NH2-terminus (SPA4CT) under conditions which allow membrane insertion. Aggregates from SPA4CT are obtained after removal of membranes by chloroform/methanol extraction or heating.
Alzheimer Disease↗
Microenvironmental factors and the binding of glycolytic enzymes to contractile filaments.
1. In reviewing the microenvironmental factors involved in the binding of the glycolytic enzymes to contractile filaments, consideration has been given to the significance of molecular crowding in maintaining these interactions under cellular conditions, and the influence of hormones, metabolites, pH and enzyme modifications on these phenomena. 2. Overall, these data serve to emphasize the biological reality of these associations, and their micro-organizational adaptations during physiological activities.
Animals↗
Ontogenic characteristics of cavian aldolase.
In order to extend the available information on the ontogenic significance of the interactions between aldolase and cellular structure, the nature and extent of these associations have been studied in the tissues of the guinea pig during development, along with analyses of the isozyme status in the bound and soluble compartments. In all tissues investigated, a significant degree of binding was evident, along with a considerable variation in the degree of association of aldolase with structure during development. Binding was particularly extensive in the early foetal stages and, in general, binding preference was directed towards A-type activity over the B- and C-type of enzyme. The significance of these ontogenic phenomena have been discussed in relation to the variations in phenotype of individual tissues during maturation and the metabolic correlations of this biphasic micro-organization.
Animals↗
Cellular differentiation and the microcompartmentation of glycolysis.
In this paper, the main features of the cellular activities of the glycolytic enzymes during growth and tissue differentiation are summarized, and correlated with the occurrence of multiple forms of these enzymes, and with their degree of interaction with subcellular structure. The substantial evidence for micro-organization of the glycolytic sequence is described, as well as its significant contribution to the diverse physiological situations encountered during development. Based on this evidence, a modular, biphasic model of glycolytic activity has been developed, with associated features of microcompartmentation and segmentation. Evidence has been provided that these phenomena play important roles in meeting the special needs of emerging cell types during early ontogeny, as well as offering the potential for increased flexibility and control of glycolysis in specialized physiological situations in the adult organism.
Animals↗
Amyloid precursor protein in aged nonhuman primates.
In individuals with Alzheimer disease and in aged nonhuman primates, deposits of amyloid occur in senile plaques in brain parenchyma and in the walls of some meningeal and cortical vessels. Amyloid is primarily composed of beta/A4, a 4-kDa peptide derived from the transmembrane form of an amyloid precursor protein (APP). We examined the distribution of beta/A4 and APP (outside the beta/A4 domain) in cerebral cortices of monkeys ranging in age from 4 to 41 years. In all animals, APP immunoreactivity was present in cell bodies, proximal dendrites, and axons of cortical neurons. In aged animals, all of which showed senile plaques, large APP-positive axons were conspicuous, and APP immunoreactivity was present in neurites around beta/A4-immunoreactive plaques. In some plaques, APP-immunoreactive elements were located in proximity to deposits of beta/A4. The presence of APP immunoreactivity in neuronal perikarya, dendrites, axons, and in neurites within beta/A4-containing plaques supports the hypothesis that neurons can serve as one source of amyloid deposited in brain parenchyma.
Aging↗
Granulomatous angiitis and cerebral amyloid angiopathy presenting as a mass lesion.
A woman, who presented with clinical and radiological signs of a right temporal mass suggestive of a brain tumour, was found to have granulomatous angiitis associated with cerebral amyloid angiopathy; the diagnosis was confirmed by biopsy. She is still well 13 years after excision of the lesion. The association of granulomatous angiitis and cerebral amyloid angiopathy constitutes a peculiar variety of central nervous system micro-angiopathy. Only a few similar cases have been described.
Amyloidosis↗
Large amounts of neocortical beta A4 deposits without neuritic plaques nor tangles in a psychometrically assessed, non-demented person.
An 88-year-old mentally normal woman (Blessed test score = 27) had very large amounts (397/mm2) of deposits stained by anti-beta A4 serum in the first temporal gyrus. Senile plaques and neurofibrillary tangles were lacking on sections stained with the Bodian's silver method, with anti-tau and anti-paired helical filament (anti-PHF) antibodies. The following beta A4 deposits were found in decreasing order of frequency: diffuse (64.8%), stellate (24.4%), primitive (10.2%), classic (0.6%) plaques. Compact plaques were not observed. Diffuse deposits predominated in layers I, III and IV. On the contrary, the rare classic plaques were located in layers II and III. No amyloid angiopathy was seen with Congo red stain although beta A 4 deposits were seen in vessel walls with immunocytochemistry. These data indicate that severe diffuse beta A4 deposits in the neocortex do not induce dementia. They suggest that the development of senile plaques composed of beta A4 amyloid and of degenerating neurites is not related solely to the density of the diffuse beta A4 deposits. Nor does it depend on the regional susceptibility of the nervous tissue since beta A4 deposits were seen in highly vulnerable cortical areas. Some other, as yet unknown, factors seem necessary. In addition, determination of beta A4 level in the neocortex is not sufficient for the diagnosis of dementia of Alzheimer type.
Aged↗
Amyloid in the brains of aged squirrel monkeys.
In this immunocytochemical study, the brains of nine squirrel monkeys (Saimiri sciureus), ranging from 8 to 27 years of age, were examined for the presence and distribution of beta/A4 amyloid, a 4-kilodalton peptide. In aged squirrel monkeys, amyloid is associated primarily with intracerebral and meningeal capillaries and arterioles and occurs to a lesser degree as small and/or diffuse deposits in the neural parenchyma and in the dense cores of senile plaques. Cerebrovascular amyloid is found primarily in neocortex, amygdala, and septum verum and is rare or nonexistent in other subcortical gray structures, white matter, cerebellum, and spinal cord; this pattern of localization is comparable to that in humans with cerebral amyloid angiopathy. There is a significant correlation between cerebrovascular and parenchymal deposits of amyloid. However, cerebrovascular amyloid is always the most abundant form in squirrel monkeys, even in cases of severe cerebral amyloidosis. In contrast to squirrel monkeys, aged rhesus monkeys (Macaca mulatta) develop mostly parenchymal deposits of amyloid and have relatively less vascular amyloid. This species difference in the histological distribution of amyloid suggests that separate mechanisms may influence the accumulation of amyloid in cerebral blood vessels and in the neural parenchyma. These data also indicate that the squirrel monkey can serve as a model for investigations of cerebrovascular amyloidosis.
Aging↗
Development of senile plaques. Relationships of neuronal abnormalities and amyloid deposits.
The evolution of senile plaques and the relationships among neuritic elements, extracellular deposits of the beta-amyloid protein (beta/A4), and vascular beta/A4 are poorly understood. Immunocytochemical methods were used to examine fixed-frozen prefrontal cortices of 14 rhesus monkeys (Macaca mulatta) (14 to 37 years of age) for the presence of abnormal fibers/neurites, alpha 1-antichymotrypsin (alpha-ACT), and beta/A4. Age-associated alterations included abnormal fibers/neurites, presence of beta/A4, and association of alpha-ACT with beta/A4 in plaques and blood vessels. Vascular amyloid was present only in the oldest monkeys. The topographic distribution of abnormal fibers/neurites was mapped with acetylcholinesterase (AChE) histochemistry, and deposits of amyloid were visualized with immunocytochemistry for beta/A4. beta/A4 often was associated with neurites, but many neurites lacked demonstrable beta/A4. Thus in aged monkeys, abnormal neurites may provide one type of focus for the accumulation of the amyloid precursor, which is subsequently abnormally processed to form beta/A4. Our data in rhesus monkeys suggest that fiber and neuritic abnormalities increase with age and that they may precede the majority of beta/A4 deposits; the initial stages of neurite formation and parenchymal amyloid deposits may be independent of the appearance of vascular amyloid; and these processes may be synergistic with advanced age.
Acetylcholinesterase↗
Interactions between glycolytic enzymes and cytoskeletal structure--the influence of ionic strength and molecular crowding.
In a study of the interactions between glycolytic enzymes and cytoskeletal structure, the effect of increasing the degree of molecular crowding by the addition of physiological concentrations of saline and protein was studied. Increasing the ionic strength to physiological levels resulted in only a slight decrease in the retention of most of enzymes, whereas the establishment of physiological concentrations of both saline and protein, caused a markedly increased degree of binding of all the glycolytic enzymes. The implications of this data have been discussed in relation to the relative affinities of interaction of the individual components, the influence of molecular crowding and the physiological significance of this phenomenon.
Animals↗
The binding of glycolytic enzymes to the cytoskeleton--influence of pH.
In a continuing study of the interactions between glycolytic enzymes and cytoskeletal structure, the influence of a variation of the pH of the eluting medium has been investigated. This treatment resulted in an increased degree of binding of most of the glycolytic enzymes with a decrease in pH, with the most marked increases in binding occurring with phosphofructokinase, glyceraldehydephosphate dehydrogenase, enolase and pyruvate kinase. The significance of this data has been discussed with reference to the relative affinities of interaction of the individual glycolytic components and the physiological correlations of these phenomena.
Animals↗
Isozymes and the micro organization of organellar structure and function.
One of the most valuable of the wide-ranging attributes of isozymes is the novel insight they allow into some of the most complex aspects of cell biology. The microorganization of subcellular structure and function is one such area, and the present study utilizes the peroxisome as an example of these applications. The biological characteristics of the major enzymic component of this organelle, catalase, have been detailed in mammalian tissues, where the enzyme exhibits a complex heterogeneity, which is due to multiple types of epigenetic modification. The major native multiplicity, however, has been demonstrated as attributable to sialic acid attachment to the enzyme. In studying the compartmentalization of these isozymes within liver cells, the technique of differential extraction with digitonin was employed, and evidence provided which supports the presence of an appreciable proportion of catalase activity in the cytoplasmic compartment. The source of these cytoplasmic isozymes was traced to release from the peroxisome, and the mechanism of this release identified with variations in the content of lysophosphatidyl choline in the peroxisomal membrane. Studies of the association of catalase with the subcellular membranes indicated an appreciable ionic interaction which varied with membrane type and isozyme status. Activity was enhanced in the bound form, providing support for the interpretation of a general protective role of this enzyme against oxidation of membrane components within the cell. Overall, these studies are considered to contribute significantly to current knowledge of the biological role and subcellular localization of catalase in relation to organellar structure and function.
Animals↗
About a peculiar disease. Interview by Gay Hudson.
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Alzheimer Disease↗
On the interactions of catalase with subcellular structure.
The interaction of mouse liver catalase with subcellular membranes was studied, and an ionic interaction with a variety of membranes, including those derived from the microsomes, was observed. The interaction with microsomal membranes was found to be abolished by pre-treatment of catalase with neuraminidase, indicating a functional significance for catalase-bound sialic acid. Catalase activity was found to be enhanced when bound to membranes, and evidence for a weak association of catalase with peroxisomal structure in mouse liver was also obtained. It is concluded that mouse liver catalase has a capacity to bind to a variety of subcellular membranes in vivo and that this interaction may be consistent with a general protective role for the enzyme, as well as being compatible with a model of peroxisomal biogenesis which involves the interaction of catalase with microsomal membranes.
Animals↗
Interactions of glycolytic enzymes.
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Erythrocyte Membrane↗