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Biomedical subjects

B Ghetti

Publications and source records attributed to B Ghetti.

At least 145 records · Page 8Linked to original sources
PubMed1992

Mutant prion proteins in Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles.

Two families with Gerstmann-Sträussler-Scheinker disease (GSS) are atypical in possessing neocortical neurofibrillary tangles (NFTs), which are few or absent in other kindreds with GSS, in addition to amyloid plaques that react with prion protein (PrP) antibodies and protease-resistant PrP accumulation in the brain. A leucine substitution at PrP codon 102 has been genetically linked to GSS in some families. We examined the PrP gene in these families. A serine for phenylalanine substitution was found at codon 198 in the Indiana patients; arginine for glutamine substitution at codon 217 in the Swedish patients. These mutations in PrP are the first to be associated with the appearance of both PrP amyloid plaques and neocortical NFTs in GSS patients.

Adult↗
PubMed1991

A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease.

Alzheimer's disease is a form of localized amyloidosis characterized by cerebral cortical amyloid plaques, neurofibrillary tangles, and amyloid deposits within the walls of leptomeningeal vessels. Although most cases of Alzheimer's disease are sporadic, kindreds with autosomal-dominant inheritance of the syndrome suggest that a single mutation may be important in pathogenesis. Direct sequencing of DNA from a family with autopsy-proven Alzheimer's disease revealed a single amino acid substitution (Phe for Val) in the transmembrane domain of the amyloid precursor protein. This mutation correlates with the presence of Alzheimer's disease in all patients in this study, and may be the inherited factor causing both amyloid fibril formation and dementia.

Alzheimer Disease↗
PubMed1991

Amyloid protein of Gerstmann-Sträussler-Scheinker disease (Indiana kindred) is an 11 kd fragment of prion protein with an N-terminal glycine at codon 58.

Gerstmann-Sträussler-Scheinker (GSS) disease is a familial neurological disorder pathologically characterized by amyloid deposition in the cerebrum and cerebellum. The GSS amyloid is immunoreactive to antisera raised against the hamster prion protein (PrP) 27-30. This is a proteinase K-resistant glycoprotein of 27-30 kd that is derived from an abnormal isoform of a neuronal glycoprotein of 33-35 kd designated PrPSc and is a molecular marker of amyloid fibrils isolated from animals with scrapie and humans with related disorders. We have purified and characterized proteins extracted from amyloid plaque cores isolated from two patients of the Indiana kindred of GSS disease. We found that the major component of GSS amyloid is an 11 kd degradation product of PrP, whose N-terminus corresponds to the glycine residue at position 58 of the amino acid sequence deduced from the human PrP cDNA. In addition, amyloid fractions contained larger PrP fragments with apparently intact N-termini and amyloid P component. These findings suggest that the disease process leads to proteolytic cleavage of PrP, generating an amyloidogenic peptide that polymerizes into insoluble fibrils. The N-terminal cleavage of PrP in GSS disease occurs at a tryptophan-glycine peptide bond identical to that cleaved by proteinase K in vitro to generate PrP 27-30 from hamster PrPSc at codon 90. Since no mutations of the structural PrP gene have been found in the Indiana family of GSS disease, it is conceivable that factors other than the primary structure of PrP play a crucial role in the process of amyloid formation and the development of clinical neurologic dysfunction.

Amino Acid Sequence↗
PubMed1991

Stabilisation of neurone number in the inferior olivary complex of aged 'Purkinje cell degeneration' mutant mice.

Virtually all cerebellar Purkinje cells degenerate in 'Purkinje cell degeneration' (pcd) mutant mice between postnatal day (P) 17 and P45. The inferior olivary complex (IOC) in these mutants undergoes atrophy subsequent to the deprivation of its major cortical target; the number of IOC neurones declines by 18% by P23 and by 49% by P300. In the present study we used control (+/?) and mutant (pcd/pcd) mice that were 14-15 months old to determine whether any further cell loss is observed in the pcd IOC after P300. Nerve cell counts were obtained from serial paraffin sections of the medulla oblongata. The corrected estimate of neurone number in the left IOC of control mice was 12,785 +/- 794 cells (mean +/- SD, n = 5); in pcd mutants that number was 6,722 +/- 535 (n = 5). The 47% difference between control and mutant mice was highly significant (p less than 0.001). The perikarya of surviving IOC neurones were atrophic. Compared to P17 mutants, pcd homozygotes manifest a 50% cell loss by P428-P446, which does not practically differ from the deficit found on P300. These results suggest that, once a critical neuronal mass degenerates in the IOC of pcd mutants, the remaining neurones become stabilised and no further loss is observed even at an advanced age.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1991

Unique cerebellar phenotype combining granule and Purkinje cell loss: morphological evidence for weaver* pcd double mutant mice.

Weaver (wv/wv) mutant mice lose most granule cells of the cerebellum during the first 2 weeks of postnatal life; 'Purkinje cell degeneration' (pcd/pcd) mutants lose virtually all Purkinje cells between postnatal days 17 and 45. Both these neurological mutations are autosomal recessive. We designed a breeding protocol that, in theory, should result in the production of mice with a doubly mutant, wv/wv*pcd/pcd, genotype. Some of the offspring of such crosses had a novel cerebellar phenotype in which both granule and Purkinje cells underwent degeneration, leading to a highly atrophic cortex. This phenotype is what would be expected in wv/wv*pcd/pcd double mutants, and the proportion of such progeny obtained fits with genetic expectations. We propose that (1) wv/wv*pcd/pcd double mutant mice are viable, and (2) the anatomical phenotype of such mice is a combined expression of the component phenotypes.

Aging↗
PubMed1991

In vitro release of endogenous dopamine from the striatum of the weaver mutant mouse.

The weaver mutant mouse has a genetically determined defect in the nigrostriatal dopaminergic system. The present study was undertaken to test the hypothesis that in the weaver mutant mouse, striatal nerve terminals undergo compensatory changes in response to this deficiency. To test this hypothesis, we studied the basal and stimulated release of dopamine from striatal slices of weaver mutant mice and matched controls. By using a superfusion system and concentrating the superfusate by passage over alumina, resting dopamine release could be determined in the weaver mutant despite the fact that striatal tissue content of dopamine in these mice is reduced by greater than 75% compared with control mice. Fractional resting release of dopamine in weaver striatal slices was significantly elevated compared with that in controls, suggesting that the release mechanisms in the weaver may be adapting to overcome the dopamine deficit. Potassium-evoked release (24 and 48 mM potassium) was not significantly different between the two genotypes. In contrast, amphetamine-evoked release (1 microM) was significantly greater in the weaver mice than in controls. In both genotypes, release evoked by amphetamine was completely inhibited by cocaine, implicating the dopamine uptake carrier in this release process. These findings suggest that fundamental differences in dopamine release mechanisms exist between weaver and control mice and support the hypothesis that compensatory mechanisms may develop in neurons in response to dopamine deficits.

Amphetamine↗
PubMed1990

Alzheimer patients and Down patients: abnormal presynaptic terminals are related to cerebral preamyloid deposits.

In Alzheimer's disease, in Down syndrome and in normal aging, scattered deposits of amyloid fibril precursors occur in both cerebral cortex and subcortical grey structures. Within such preamyloid deposits, no degenerating neurites with paired helical filaments have ever been observed. This study, carried out on brains from Alzheimer patients and Down patients, reports on the relationship between preamyloid deposits and neuritic changes. These changes were represented by presynaptic terminal swellings immunolabeled by antisynaptophysin and antiubiquitin antibodies, not by Alz50. These findings support the view that the deposition of amyloid fibril precursors in the neuropil is closely related to presynaptic terminals, although whether the former precedes or follows the development of presynaptic terminal changes is still undetermined.

Adult↗
PubMed1990

Neurofibrillary tangles of the Indiana kindred of Gerstmann-Sträussler-Scheinker disease share antigenic determinants with those of Alzheimer disease.

In the Indiana kindred of Gerstmann-Sträussler-Scheinker disease, neurofibrillary tangles (NFT) with paired helical filaments (PHF) are numerous, widespread and consistently present in the cerebral cortex and several subcortical nuclei. Such tangles share antigenic determinants with those of Alzheimer disease; in fact, they are recognized by Alz50, anti-PHF and anti-ubiquitin antibodies. Thus, NFT with structural and immunocytochemical similarities are present in two distinct forms of amyloidosis of the central nervous system, i.e. the Indiana kindred of Gerstmann-Sträussler-Scheinker disease and Alzheimer disease.

Aged↗
PubMed1990

Intrastriatal implants of mesencephalic cell suspensions in weaver mutant mice: ultrastructural relationships of dopaminergic dendrites and axons issued from the graft.

Dissociated cell suspensions were prepared from the ventral midbrain of normal mouse foetuses and stereotaxically implanted into the neostriatum of 2-3 months old homozygous weaver mutant mice, which are severely deficient in dopamine. In tests of amphetamine-induced turning behaviour 60 days after grafting, recipient animals displayed a rotational bias opposite to the grafted side. Prior to perfusion, which was carried out at 80 days after transplantation surgery, the grafted striata of the weaver recipients were deprived of their intrinsic mesostriatal dopamine input by local injections of 6-hydroxydopamine into the ipsilateral substantia nigra in order to selectively study the innervation derived from the graft. Grafts were found to contain an estimated 100-700 tyrosine hydroxylase immunoreactive neurones. An ultrastructural analysis demonstrated that both axons and dendrites immunoreactive for tyrosine hydroxylase extended from the graft into the recipient striatum. In the host striatum proximal to the graft (i.e. at a distance of 0.0-0.5 mm from the graft) the proportion of dendrites to axons was about 1:2, whereas distal to the graft (i.e. at a distance of 0.5-1.0 mm) it was 1:20. Graft-derived tyrosine hydroxylase immunoreactive axons were primarily found in apposition with unlabelled dendrites or spines of the recipient striatum (greater than 90%). Graft-derived dopaminergic dendrites received synaptic input from unlabelled axon terminals and were opposed to the unlabelled somata of striatal neurones in a few instances. In conclusion, this study shows that mesencephalic cell suspensions survive in the weaver striatum and provide a functional dopamine innervation which comprises both axonal and dendritic processes.

Animals↗
PubMed1990

Age-related changes in striatal dopamine D2 receptor binding in weaver mice and effects of ventral mesencephalic grafts.

Dopamine (DA) D2 receptor binding is increased in the striatum of 5-6 months old weaver mutant mice (Kaseda et al. 1987). This may occur in response to the loss of DA neurons in the midbrain and the decrease in DA content in the striatum of homozygous mutants. One purpose of the present study was to determine if the diminished DA innervation is associated with changes in D2 receptors at earlier ages and if the increase in DA D2 receptor binding seen at 5-6 months is a lasting phenomenon. Specific [3H]spiperone binding was measured in the dorsolateral (DL), dorsomedial (DM) and ventrolateral (VL) striatum and in the nucleus accumbens (AC) of homozygous weaver mutant mice (wv/wv), heterozygous littermates (wv/+) and wild-type controls (+/+). Mice were studied at 20 days and 1, 3, 6, 9 and 12 months of age. The difference in specific [3H]spiperone binding in DL striatum between wv/wv and +/+ mice was significantly greater at 6 months than the difference at 1 month and at 12 months of age. Foetal ventral mesencephalic grafts survive and establish functional innervation in the striatum of weaver mice as shown by the induction of a contralateral turning bias (Low et al. 1987). The second aim of the present studies was to determine if such grafts would also reverse the increase in DA D2 receptor binding in the striatum. Aspiration cavities were prepared in the cortex of weaver mice, and ventral mesencephalic tissue from E14-E15 +/+ foetuses was subsequently placed on the surface of the right dorsal striatum when the recipients were 3 months old.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1989

The dendritic dopamine projection of the substantia nigra: phenotypic denominator of weaver gene action in hetero- and homozygosity.

While cerebellar granule cell migration and survival are affected by the weaver (wv) mutation both in the heterozygous and homozygous states, the dopamine (DA) deficit of the nigrostriatal projection has been shown to involve only midbrain DA cell bodies and nigrostriatal DA axons of homozygous mutants. We have identified a cellular site which is defective in the mesencephalic DA system of mice both heterozygous and homozygous for the wv gene. That deficit involves the dendritic DA projection which extends from the substantia nigra pars compacta (SNc) into the pars reticulata (SNr). In the midbrain of heterozygotes, dopaminergic dendrites are reduced by 60% at 20 days of age, when DA neurone number in the midbrain, DA content in the neostriatum and pattern of synaptic connectivity of nigrostriatal axon terminals are normal. At the same age, the deficit of dopaminergic dendrites in the SNr of homozygotes (76%) is disproportionate to the loss of DA cell bodies (42%). These findings: (a) may provide clues to the aetiopathogenetic mechanisms of wv gene operation; and (b) may explain the generalised convulsions intermittently manifested by weaver heterozygotes, as the SN has been implicated in the pathophysiology of experimental seizures.

Animals↗
PubMed1989

Alzheimer patients: preamyloid deposits are more widely distributed than senile plaques throughout the central nervous system.

In Alzheimer's disease, anti-beta-protein antisera label not only amyloid deposits accompanied by degenerating neurites (neuritic and mature plaques) and amyloid deposits without degenerating neurites, but also preamyloid deposits lacking the optical properties of amyloid fibrils. We have carried out a study of the brains of 13 patients with Alzheimer's disease (one with the familial and 12 with the sporadic form), using anti-beta-protein and anti-paired helical filament antisera, thioflavine S, Congo red and Gallyas' silver impregnation, in order to determine whether the distribution of preamyloid deposits and amyloid deposits without degenerating neurites differs from that of amyloid deposits with degenerating neurites. Preamyloid deposits and amyloid deposits with or without degenerating neurites were present in cortex, neostriatum, medial geniculate body and thalamic (anterior and extralaminar) nuclei, whereas preamyloid deposits and amyloid deposits without degenerating neurites, but not amyloid deposits with degenerating neurites, were present in other thalamic nuclei, in the globus pallidus, brainstem, cerebellar cortex and upper spinal cord. These results support the view that preamyloid deposits evolve to senile (neuritic and mature) plaques only in specific brain regions, where neurites vulnerable to amyloid fibrils are widely distributed.

Adult↗
PubMed1989

Developmental expression of polypeptide PEP-19 in cerebellar cell suspensions transplanted into the cerebellum of pcd mutant mice.

Cerebellar cell suspensions were prepared from normal mouse embryos and implanted into the cerebellum of Purkinje cell degeneration (pcd) mutant mice, which are characterized by a virtually complete degeneration of Purkinje cells between postnatal day (P) 17 and P45. The expression of immunoreactivity for PEP-19, a developmentally-regulated brain-specific polypeptide, was analyzed in normal mouse cerebellum, as well as in pcd mutants with or without grafts. In the normal cerebellum, PEP-19 immunoreactivity was present in Purkinje cells. In unoperated mutants, 45 days of age or older, Purkinje cells were absent. In grafted pcd mice, numerous PEP-19 immunoreactive, neuroblast-like cells were seen in the graft at 5 days after transplantation. By 9 days, large PEP-19 immunoreactive neurons were found in the host molecular layer; by 17 days after transplantation, such neurons displayed an extensive dendritic tree and resembled differentiated Purkinje cells. The vast majority of PEP-19 immunoreactive cells was located in the molecular layer of the host at 9 days after transplantation and beyond; nonetheless, the same cells extended axonal processes toward the graft, indicating an affinity for co-grafted (possibly deep nuclei) neurons. These results point to the ability of donor Purkinje cells for survival, migration into the host brain and morphological and chemical differentiation following transplantation to the degenerated cerebellar cortex of the recipient mutants.

Animals↗
PubMed1989

Degeneration and graft-induced restoration of dopamine innervation in the weaver mouse neostriatum: a quantitative radioautographic study of [3H]dopamine uptake.

A recently introduced quantitative radioautographic technique was used to characterize the striatal dopaminergic deficit in weaver mutant mice and to evaluate the extent of DA reinnervation resulting from cell suspension grafts of fetal ventral mesencephalic tissue. Brain slices from normal mice and unilaterally grafted weaver mice were incubated in [3H]DA, in the presence of desipramine and pargyline 3-5 months after graft surgery. Semi-thin sections from the fixed and resinembedded slices were subsequently exposed on tritium sensitive film and afterwards dipped in nuclear emulsion for light microscope radioautography. Alternative slices were embedded in Epon for post-embedding tyrosine hydroxylase (TH) immunocytochemistry. The grain density of the film radioautographs matched well the distribution of TH positive fibers. Both methods revealed an almost complete absence of DA axons in the dorsomedial quadrant of the weaver neostriatum and an increasing density of DA innervation towards the ventrolateral areas. In the light microscope radioautographs, only the ventral striatum (i.e. nucleus accumbens and olfactory tubercle) and a narrow ventral and periventricular zone of the caudate-putamen were covered by silver grain clusters typical of DA varicosity labeling. Such labeled varicosities were nevertheless found in reduced numbers the lateral portion of both nucleus accumbens and the olfactory tubercle. The remaining neostriatum was overlaid by diffuse silver grains. suggesting a deficient DA uptake and storage mechanism in the residual DA fibers in this region. Immunocytochemistry using antibodies specific for DA or TH provided further evidence that the residual DA innervation in the weaver neostriatum was biochemically defective. Weaver mice with grafts of ventral mesencephalic tissue in the right neostriatum showed an amphetamine-induced rotational bias to the contralateral side, which was not seen in the sham-operated animals. In contrast to the intrinsic weaver neostriatal DA innervation, DA fibers of graft origin exhibited the normal, clustered type of varicosity labeling. The computerized image analysis of silver grain density in film radioautographs was calibrated by counting these labeled varicosities in selected areas of light microscope radioautographs from the same sections. Results showed a mean DA reinnervation of neostriatal tissue surrounding the graft of about 20%, in some cases up to 80%, of the density seen in wild type mice, with a gradual decrease with distance up to 1-1.4 mm from the graft. The ventral parts of the neostriatum, which contained higher numbers of residual intrinsic DA fibers, were much more sparsely reinnervated than the dorsal and dorsomedial areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphetamines↗
PubMed1989

Gerstmann-Sträussler-Scheinker disease. I. Extending the clinical spectrum.

We present the clinical findings in affected members of a large kindred with Gerstmann-Sträussler-Scheinker disease. Sixty-four patients exhibited progressive ataxia, dementia, and parkinsonian features. Inheritance appears to be autosomal dominant. Impaired smooth-pursuit eye movements, defective short-term memory, clumsiness of the hands, and ataxia of gait develop in the late 30s to early 60s. Eye movement abnormalities are characteristic of cerebellar dysfunction. Dementia progresses gradually over several years. Later, rigidity and bradykinesia appear and, at this stage, there is often psychosis or severe depression with rapid weight loss. Death occurs in 6 months to 2 years after onset of rigidity. Magnetic resonance imaging in 2 affected individuals showed cerebellar atrophy. There is decreased T2 signal in the basal ganglia, consistent with iron deposition.

Adult↗
PubMed1989

Gerstmann-Sträussler-Scheinker disease. II. Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family.

Azzarelli et al reported an Indiana kindred affected by a hereditary disorder, characterized clinically by ataxia, parkinsonism, and dementia. Recently, we studied neuropathologically the 3rd and 4th cases that came to autopsy among the patients of this family. As in 2 patients examined previously, amyloid plaques were widespread throughout the cerebrum and the cerebellum, whereas neurofibrillary tangles were numerous in the cerebral cortex, the hippocampus, and the substantia innominata. Amyloid plaques were not recognized by polyclonal antibodies against the Alzheimer's disease amyloid A4 protein, but did contain epitopes recognized by antibodies against a prion protein. Spongiform changes were occasionally observed and were mild. Our findings indicate that this familial disorder is a form of or is related to Gerstmann-Sträussler-Scheinker disease. The consistent presence of numerous neurofibrillary tangles may be important in differentiating a distinct subgroup of patients with familial Gerstmann-Sträussler-Scheinker disease, and indicates that a disturbance of the cytoskeleton might be part of the neuronal pathology of Gerstmann-Sträussler-Scheinker disease.

Amyloid↗