Review and hypothesis: Alzheimer disease and Down syndrome--chromosome 21 nondisjunction may underlie both disorders.
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Aging↗
Biomedical subjects
H Potter
Publications and source records attributed to H Potter.
Alpha 1-antichymotrypsin is present together with the beta-protein in monkey brain amyloid deposits.
The recent finding that the serine protease inhibitor, alpha 1-antichymotrypsin, is tightly associated with the amyloid deposits in brains of normal aged individuals and patients with Alzheimer's disease [Abraham C. R., Selkoe D. J. and Potter H. (1988) Cell 52, 487-501], suggests a role for this inhibitor in the progressive deposition of brain amyloid in humans. We have used immunocytochemistry to detect alpha 1-antichymotrypsin in the amyloid that accumulates in brains of aged monkeys, a naturally occurring animal model of Alzheimer-like neuropathology. In monkeys of increasing age, the earliest alpha 1-antichymotrypsin immunoreactivity was found in cortical perivascular cells, before the appearance of either Thioflavin S-detectable amyloid deposits or beta-protein reactivity in the vessel walls. Subsequently, amyloid deposits appeared in small meningeal blood vessels and cortical neuritic plaques. The oldest monkeys also showed microvascular amyloid in the cortical gray matter. Amyloid was never seen in white matter. The amyloid deposits in meningeal vessels were always positive for both beta-protein and alpha 1-antichymotrypsin, whereas in the cortex, alpha 1-antichymotrypsin immunoreactivity seemed to appear somewhat later than that of beta-protein. These findings demonstrate that two of the brain amyloid components of human senescence and Alzheimer's disease--the beta-protein and the protease inhibitor alpha 1-antichymotrypsin--are also present in the amyloid deposits of normal aged monkey brain. The extended molecular parallels between normal brain aging and Alzheimer's disease suggest that similar biochemical mechanisms may underlie progressive amyloid deposition in both situations.
Aging↗
The protease inhibitor, alpha 1-antichymotrypsin, is a component of the brain amyloid deposits in normal aging and Alzheimer's disease.
The purpose of this study was to characterize the nature and the origin of the Alzheimer's disease amyloid deposits. We used an amyloid antiserum to screen a human liver expression library. A positive clone was sequenced and found to code for the serine protease inhibitor alpha 1-antichymotrypsin, an acute phase serum protein. Thus, this protein is a second component of the brain amyloid in addition to the beta-protein. In order to determine whether the inhibitor originated from the serum or was made in the brain, we performed Northern blots on tissue from control and Alzheimer brain and found that alpha 1-antichymotrypsin RNA is present in the brain and that the diseased brain contained larger amounts than the controls. Immunocytochemistry and in situ hybridization show the astrocytes to produce the inhibitor, mainly around senile plaques, alpha 1-antichymotrypsin is only associated with the amyloid deposits of the beta-protein kind in normal aging of man and monkeys. Alzheimer's, Down's syndrome and hereditary cerebral hemorrhage with amyloidosis of Dutch origin, but not in primary and secondary amyloidosis or familial amyloidotic polyneuropathy. The specific association between alpha 1-antichymotrypsin and the beta-protein prompted us to suggest a role for this serine protease inhibitor in the proteolytic processing of the beta-protein precursor.
Aging↗
Alpha 1-antichymotrypsin in brain aging and disease.
The recent finding (Abraham et al., 1988) that the serine protease inhibitor, alpha 1-antichymotrypsin, is tightly associated with the amyloid deposits of normal aged and Alzheimer's disease brains, suggests a role for this inhibitor in the amyloid deposition. We used immunohistochemistry to analyze the presence of alpha 1-antichymotrypsin in the similar brain amyloid which accumulates in monkeys with increasing age. The earliest alpha 1-antichymotrypsin immunoreactivity was found in cortical perivascular cells before the appearance of either thioflavin S-identifiable amyloid deposits or beta-protein reactivity in vessels. The cortical amyloid, both in senile plaques and vasculature, was seen only several years later, and could be stained for both beta-protein and alpha 1-antichymotrypsin. In addition, we analyzed the association of alpha 1-antichymotrypsin with the other types of amyloidoses. alpha 1-antichymotrypsin antibodies immunolabeled only amyloid deposits that have as their major component the beta-protein: normal aging, Alzheimer's disease, Down's syndrome and in the hereditary cerebral hemorrhage with amyloidosis of Dutch origin (HCHWA-D), but not in Creutzfeldt-Jakob disease, Familial Amyloidotic Neuropathy, primary amyloidosis, or secondary amyloidosis. Lastly, we used immunocytochemistry to identify cells that express alpha 1-antichymotrypsin during brain degeneration. Such immunoreactivity was found in astrocytes near areas of neuronal or tissue loss, in pericytes and in a few neurons, even in diseases with no alpha 1-antichymotrypsin-containing amyloid deposits. In summary, alpha 1-antichymotrypsin is found in three cell types in various brain diseases. In amyloid deposits it is found only in association with the beta-protein, further strengthening its possible role in the processing of the beta-protein precursor or the stability of the beta-protein amyloid deposits.
Aging↗
Astrocytes in Alzheimer's disease gray matter express alpha 1-antichymotrypsin mRNA.
The serine protease inhibitor alpha 1-antichymotrypsin (ACT) has been shown to be tightly associated with the amyloid found in plaque cores and blood vessels in the brains of patients with Alzheimer's disease (AD). Although the ACT found in plaques could be derived from the high levels of ACT in serum, previous Northern analysis revealed that ACT mRNA is produced locally in AD gray matter at much higher levels than in control gray matter. To determine which brain cells express ACT mRNA, we conducted in situ hybridization with 35S-labeled cRNA probes on hippocampal sections from four AD and three control cases. To identify astrocytes unequivocally, some of the hybridized sections were immunostained for glial fibrillary acidic protein, which is astrocyte-specific. Our results showed numerous astrocytes that were intensely labeled by the probe for ACT mRNA throughout the subicular gray matter of the AD cases. In contrast, astrocytes in control gray matter were rarely labeled by the probe for ACT mRNA. Examination of plaque cores in the AD subiculum showed that some astrocytes intensely labeled by the probe for ACT mRNA were closely associated with virtually every plaque core. Our results also showed many astrocytes in both AD and control white matter that were intensely labeled by the probe for ACT mRNA, and a small fraction of the astrocytes in a juvenile cerebellar astrocytoma that we examined were found to produce high levels of ACT mRNA. In every area in which astrocytes expressing ACT mRNA were found, astrocytes producing no detectable ACT message were also present. Our findings indicate that astrocytes produce the increased ACT mRNA in AD gray matter observed by Northern analysis, but they also show that ACT mRNA expression by astrocytes is not unique to AD. The presence of astrocytes expressing ACT mRNA near, and extending processes towards, plaque cores strongly suggests that some if not all of the ACT associated with amyloid plaque cores is produced by astrocytes surrounding the cores.
Alzheimer Disease↗
Electroporation in biology: methods, applications, and instrumentation.
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Cell Membrane↗
Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease.
Two approaches--molecular cloning and immunochemical analysis--have identified one of the components of Alzheimer's disease amyloid deposits as the serine protease inhibitor alpha 1-antichymotrypsin. An antiserum against isolated Alzheimer amyloid deposits detected immunoreactivity in normal liver. The antiserum was then used to screen a liver cDNA expression library, yielding three related clones. DNA sequence analysis showed that these clones code for alpha 1-antichymotrypsin. Antisera against purified alpha 1-antichymotrypsin stained Alzheimer amyloid deposits, both in situ and after detergent extraction from brain. The anti-amyloid antiserum recognizes at least two distinct epitopes in alpha 1-antichymotrypsin, further supporting the presence of this protein in Alzheimer amyloid deposits. In addition to being produced in the liver and released into the serum, alpha 1-antichymotrypsin is expressed in Alzheimer brain, particularly in areas that develop amyloid lesions. Models by which alpha 1-antichymotrypsin could contribute to the development of Alzheimer amyloid deposits are discussed.
Alzheimer Disease↗
Hyperthermic suppression of a genetically programmed melanoma in hybrids of fishes: genus Xiphophorus.
In fishes of the genus Xiphophorus, hybrid offspring of the spotted dorsal female platyfish, X. maculatus, and male swordtails, X. helleri, are genetically programmed to develop melanoma when raised at ambient laboratory temperatures. When these hybrid offspring were raised under hyperthermic conditions, there was no development of melanoma. Electron microscopy revealed degenerative changes in the melanocytes of heat-treated hybrids not seen in hybrids raised at ambient temperatures. The platyfish-swordtail melanoma system represents an appropriate model for the investigation of the relationship between hyperthermia and melanoma formation and treatment in poikilothermic vertebrates.
Adaptation, Physiological↗
Retrovirus-like particles in embryonic kidney tissue of the platyfish, Xiphophorus maculatus.
Ultrastructural studies were performed on embryos of an inbred strain (163A) of the platyfish Xiphophorus maculatus, and a pooled stock of the Rio Sarabia strain of the swordtail, X. helleri. Viral-like particles were found in the kidney tissue of platyfish embryos. Exposure of pregnant platyfish to 5-bromodeoxyuridine during the time of differentiation of embryonic melanocytes enhanced the production of viral-like particles in platyfish embryos. Viral-like particles were not found in untreated or drug-treated swordtail embryos. The morphology of these particles corresponds to type C retroviruses.
Animals↗
A 'Southern Cross' method for the analysis of genome organization and the localization of transcription units.
A 'Southern Cross' hybridization method is described which permits the rapid restriction mapping of DNA molecules, up to 40 kb in size, for at least ten enzymes in a single operation. The procedure allows the full set of 32P-end-labelled fragments derived from one restriction enzyme digest to intersect and attempt to hybridize to the gel-separated fragments of as many as ten unlabelled digests immobilized on parallel sheets of filter paper. A two-dimensional array of hybridization spots is revealed on each recipient paper, indicating which radioactive and non-radioactive DNA fragments have sequences in common. A restriction map can then be directly and simply deduced from the matrix of hybridization spots in each cross-blot. The method affords advantages over other procedures for obtaining restriction maps in terms of the time required, the number of restriction enzymes that can be mapped, and the potential for eliminating ambiguity. It is also sufficiently sensitive to detect DNA rearrangements and restriction-site polymorphisms in moderately complex genomes. Furthermore, the procedure is applicable to other aspects of the study of genome organization: for example, the exon and intron areas of a segment of cloned genomic DNA can be identified by cross-hybridizing a set of radioactive restriction fragments from the genomic clone against immobilized RNA from a cell type of interest.
DNA Restriction Enzymes↗
Cell-specific expression of the human parathyroid hormone gene in rat pituitary cells.
The promoter region of the human parathyroid hormone gene was fused to the Escherichia coli neo gene and introduced into GH4C1 rat pituitary and human HeLa cells. Both TATA boxes of the human parathyroid hormone gene accurately directed transcription in GH4C1 cells; the parathyroid hormone promoter was inactive in HeLa cells.
Animals↗
Enhancer-dependent expression of human kappa immunoglobulin genes introduced into mouse pre-B lymphocytes by electroporation.
We have developed a general method for introducing cloned genes into mammalian cells that affords substantial benefits over current technology. It is simple, rapid, and applicable to many (perhaps all) cell types, including those that are refractory to traditional transfection procedures. The method involves exposure of a suspension of cells and cloned DNA to a high-voltage electric discharge. In a model application of this transfection procedure, we have studied the expression of cloned human and mouse Ig kappa genes stably introduced into mouse pre-B cells and fibroblasts. We find that there is a B-cell-specific enhancer-activator region in the J-C intron of the human kappa gene that is necessary for efficient transcription of the cloned gene in mouse pre-B lymphocytes. This suggests that both the DNA element and the proteins required for its regulatory activity have been highly conserved in evolution and that these elements operate at the pre-B-cell stage of immunocyte development, a stage that precedes productive kappa gene rearrangement.
Animals↗
Translocations among antibody genes in human cancer.
The characteristic chromosomal translocations that occur in certain human malignancies offer opportunities to understand how two gene systems can affect one another when they are accidentally juxtaposed. In the case of Burkitt lymphoma, such a translocation joins the cellular oncogene, c-myc, to a region encoding one of the immunoglobulin genes. In at least one example, the coding sequence of the rearranged c-myc gene is identical to that of the normal gene, implying that the gene must be quantitatively, rather than qualitatively, altered in its expression if it is to play a role in transformation. One might expect to find the rearranged c-myc gene in a configuration that would allow it to take advantage of one of the known immunoglobulin promoters or enhancer elements. However, the rearranged c-myc gene is often placed so that it can utilize neither of these structures. Since the level of c-myc messenger RNA is often elevated in Burkitt cells, the translocation may lead to a deregulation of the c-myc gene. Further, since the normal allele in a Burkitt cell is often transcriptionally silent in the presence of a rearranged allele, a model for c-myc regulation is suggested that involves a trans-acting negative control element that might use as its target a highly conserved portion of the c-myc gene encoding two discrete transcriptional promoters.
Base Sequence↗
The human c-myc oncogene: structural consequences of translocation into the IgH locus in Burkitt lymphoma.
We have determined the sequence of the normal human c-myc gene and compared it to portions of a c-myc gene that has been translocated into the immunoglobulin heavy chain locus in a Burkitt lymphoma cell. The normal c-myc gene is encoded in three discrete exons divided by two large intervening sequences. Its mRNA is transcribed from two active promoters located about 150 nucleotides from one another. Each promoter initiates transcription of a long (approximately 550 bp) untranslatable leader sequence encoding the entire first exon. This exon and additional 5' flanking sequences are tightly conserved between mouse and man. In the Burkitt cell BL22, the rearranged c-myc gene retains both promoters and is unchanged in its amino acid coding domains. Translocation of this gene joins it to the immunoglobulin heavy chain switch region at a point approximately 1000 bp 5' to the dual c-myc promoters. These genes are joined in opposite transcriptional orientation. The structure of the translocated gene and the nature of its linkage to the immunoglobulin locus and the presence of two c-myc promoters and consequently two long leader sequences raise novel possibilities for the activation of an oncogene.
Amino Acid Sequence↗
Selective olfactory deficits in case H.M.
A variety of olfactory capacities were evaluated in H.M., a patient with bilateral medial temporal lobe resection. He demonstrated normal performance on a battery of tests of odour detection, discrimination of intensity, and adaptation. In striking contrast, H.M. was unable to discriminate or identify odours in same-different discriminations and in matching-to-sample tasks. Although he could name common objects using visual or tactile cues, he could not identify them by smell. These results indicate that the perceptual phenomena of odour detection and discrimination are dissociable by cerebral damage, and that structures in the medial temporal lobe play a critical role in odour discrimination.
Brain Diseases↗
Molecular mechanisms in genetic recombination.
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Animals↗
Mechanisms in generalized genetic recombination.
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Bacterial Proteins↗